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GBA Variants and Parkinson Disease: Mechanisms and Treatments

Laura Smith, Anthony H. V. Schapira

Cells · 2022 · Review · CC BY

doi:10.3390/cells11081261

Abstract

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 19, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting over 3% of the population aged over 65 years. The disease is characterised by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intraneuronal proteinaceous inclusions, named Lewy bodies. Towards the end of the 20th century, reports began to emerge associating the lysosomal storage disorder Gaucher disease (GD) with PD. GD is an inherited disorder caused by homozygous mutations in the GBA gene, which encodes glucocerebrosidase (GCase), a lysosomal hydrolase enzyme which catalyses the catabolism of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Since then, several large cohort studies have further investigated the link between GBA mutations and the risk of developing PD. Approximately 5–15% of PD patients have GBA mutations, making them the most important genetic risk factor for PD, occurring more frequently than other genes associated with familial PD including LRRK2, SNCA and PARK2.

Over 300 pathogenic GBA mutations have been identified. These have been associated with loss- and gain-of-function mechanisms. A persistent lack of GCase activity may influence the autophagic-lysosomal pathway (ALP) and has been associated with aggregation of alpha-synuclein. The presence of mutant GCase protein can exert toxic gain-of-function pathways including endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Dysfunction of mitochondria, the inflammatory pathway and lipid homeostasis have also been implicated in GBA-associated PD (GBA-PD) and can contribute to the pathogenic accumulation of alpha-synuclein.

In this review, we discuss how GBA mutations are associated with PD and outline the possible mechanisms involved in the pathogenesis of the disease. Advances in the understanding and identification of the underlying pathways leading to alpha-synuclein accumulation and subsequent neurodegeneration in GBA-PD will provide new avenues to be targeted for the development of more efficacious therapies for patients.

2. Parkinson Disease

PD is a common neurodegenerative disorder associated with motor and non-motor symptoms. PD patients exhibit a classic triad of motor symptoms including bradykinesia, rigidity and resting tremor. A spectrum of clinically significant non-motor symptoms has also been described. These include cognitive decline, sleep disturbances, hyposmia and psychiatric symptoms. It is suggested that at the onset of motor symptoms and PD diagnosis, dopamine neurons in the SNpc are reduced up to 60%.

A key feature of PD is the presence of aggregated protein inclusions, Lewy bodies. Lewy bodies are composed of more than 300 proteins, with alpha-synuclein reported to be the most abundant. Braak et al. proposed a sequential model of Lewy body formation and deposition of alpha-synuclein. This starts at the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus and then spreads progressively to involve the brain stem and the cortex. The processes by which Lewy body pathology arises and their role in neurodegeneration remain elusive. The leading hypothesis suggests that the pathway of intraneuronal alpha-synuclein aggregation begins with the accumulation of unfolded monomeric species, which can transform into early folded aggregate intermediates and assemble into later-stage β-sheet-rich oligomers, protofibrils and, finally, mature amyloid-like fibrils. It is these fibrils that are the basis of Lewy body formation. Fibrils have long been considered the most toxic alpha-synuclein species, exerting toxicity through several mechanisms including membrane permeability, altered autophagy and mitochondrial dysfunction. However, mounting evidence now indicates that pre-fibrillar forms of alpha-synuclein, such as oligomers, are more critical in the toxicity of alpha-synuclein. Alpha-synuclein oligomers are thought to be the most bioactive and cytotoxic form, causing neuronal dysfunction and death.

Once aberrant alpha-synuclein accumulates inside a cell, it can either be degraded, deposited in inclusions such as Lewy bodies or released into the extracellular space. These processes may be related to the failure of the cell to properly degrade alpha-synuclein by the ALP. In human brains with sporadic PD, there is evidence of autophagic and lysosomal dysfunction. This may lead to improper clearance of alpha-synuclein and its subsequent accumulation and aggregation. Another hypothesis arises from evidence of the uptake of extracellular alpha-synuclein fibrils by cells, which may propagate the spread of alpha-synuclein pathology and act as a template for misfolded, aggregated alpha-synuclein species.

3. The GBA Gene

The GBA gene is located on chromosome 1 (1q21) and is made up of 11 exons. It encodes for the lysosomal hydrolyse enzyme glucocerebrosidase (GCase) (IUBMB enzyme nomenclature number EC 3.2.1.45). The role of GCase is to cleave glycosphingolipids (GSLs) GlcCer and GlcSph into glucose and ceramide, and glucose and sphingosine, respectively. Following its trafficking to the lysosome by the transporter protein LIMP2, GCase catalyses at optimal activity upon interacting with Saposin C, a co-factor, and negatively charged lipids.

The mature GCase protein is composed of 497 residues and is between 59 and 69 kilodaltons depending on post-translational modifications. It is made up of three non-continuous domains: domain I is an antiparallel β-sheet, with two disulphide bridges which may aid proper protein folding; domain II resembles an immunoglobulin fold made up of eight β-sheets; and domain III is composed of a (β/α)8 triosephosphate isomerase (TIM) barrel and houses the active site (Figure 1).

Homozygous mutations in GBA cause Gaucher disease (GD), the most common sphingolipidosis lysosomal storage disorder. GD is a rare, autosomal recessive disease affecting approximately 1 in 800 live births within the Ashkenazi Jewish population. Its incidence is lower in the non-Ashkenazi population. Clinically, GD presents as the widespread accumulation of GlcCer and GlcSph within the lysosomes of many cell types, particularly macrophages, across several tissues and organs. It is classified into three subtypes based upon the involvement of the central nervous system (CNS). Type 1 GD is the most common variant and can manifest at any age; this phenotype is normally referred to as non-neuronopathic as it does not usually have any CNS involvement. Types 2 and 3 typically present a more severe clinical phenotype, with disease onset occurring in early life and patients often dying young. These subtypes are often referred to as neuronopathic as they affect the CNS; however, there is a wide spectrum of clinical manifestations across the entire GD subtypes, which suggests that there may be neurological involvement across the whole disease. Neuropathological analysis of type 2 GD patient brains demonstrated neuronal cell loss and astrogliosis, which was absent in type 1 GD patient brains. In the same study, four patients had type 1 GD with parkinsonism, and intraneuronal alpha-synuclein inclusions were observed. Co-cultures of astrocytes and midbrain dopamine neurons from type 1 and type 2 GD patients revealed reduced GCase activity and GlcCer and GlcSph accumulation, which were accompanied by increased alpha-synuclein aggregates when treated with extracellular alpha-synuclein monomers and fibrils, as well as inflammation. These findings suggest a link between alpha-synuclein and GBA.

The treatments available for GD are enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). ERT replaces GCase through the administration of recombinant GCase enzymes; these enzymes often have modifications to their terminal mannose residues, allowing for better targeting to and uptake into macrophages. SRT prevents the synthesis of GlcCer and GlcSph, helping to reduce substrate accumulation.

4.1. The Link between GBA Mutations and PD

Interest in the GBA gene as a genetic risk factor for PD arose in the 1980s when clinicians noticed a number of type 1 GD patients developed parkinsonism. Since then, several large cohort studies have further investigated the link between GBA mutations and the risk of developing PD. Further studies have indicated that approximately 5–15% of sporadic PD patients carry a GBA mutation, with an overall odds ratio of 5.4 (n = 7023). This makes GBA mutations numerically the most important genetic risk factor for PD identified to date.

In the normal population, PD occurs in 3–4% of individuals. However, in type 1 GD patients, this prevalence is increased. Interestingly, there does not seem to be a difference between the risk associated with GD patients and heterozygous mutation carriers. It has been estimated that GD patients have a 9.1% chance of developing PD before age 80 years (n = 504), although other studies place this as high as 20–30%. Heterozygote GBA mutation carriers are just as likely to develop PD before the age of 80, with a US study estimating 7.7% of carriers will develop PD (n = 781), while 15% was estimated in a UK cohort (n = 220). In one study of postmortem brains of PD patients, GBA mutations were present in 12 of the 57 samples (21%). These were both homozygous and heterozygous mutations, further confirming that both types are associated with PD.

The frequency of GBA mutations varies among different ethnic groups. In the European non-Ashkenazi Jewish population, the frequency is 2.9–12%, whereas in the European Ashkenazi Jewish population, it is 10–31% (n = 5691). This is much higher than in the general population, where <1% of healthy individuals are GBA mutation carriers. In the Asian population, 1.8–8.7% of people have GBA mutations (n = 8836), and 2.9–8% of North and South Americans have GBA mutations (n = 2371).

It must be noted, however, that only a minority of GD patients or GBA mutation carriers will develop PD. Mutations in the GBA gene do not cause a Mendelian form of PD; they are a genetic risk factor and increase the risk of developing PD 5–30-fold, depending on age, ethnicity and mutations included in analysis. Currently, studies are underway to assess prodromal symptoms of PD in large cohorts of GBA mutation carriers to aid in earlier diagnosis and potentially allow researchers to predict who will go on to develop PD. Furthermore, GBA mutations have been associated with dementia with Lewy bodies, providing further evidence for a link between GBA and alpha-synucleinopathies.

4.2. Presentation of GBA-PD

GBA-PD is clinically non-distinguishable from sporadic PD, aside from an earlier age at onset and more cognitive dysfunction. On average, the onset of GBA-PD is 5 years earlier than sporadic PD.

Much like sporadic PD, GBA-PD exhibits the triad of cardinal motor symptoms, although progression is more rapid. Non-motor symptoms have been reported to be more common and severe in GBA-PD compared to non-carriers, with patients often having more advanced clinical decline, with a greater risk for earlier and more prevalent cognitive impairment. Non-motor symptoms can include reduced cognition, depression, sleep disturbances and anosmia.

The pathology of GBA-PD is identical to that of sporadic PD with nigrostriatal dopamine loss and the presence of deposits of aggregated alpha-synuclein in the form of Lewy bodies in the brainstem and cortex. Some reports suggest that brains from PD patients with GBA mutations exhibit a more diffuse pattern of Lewy body distribution throughout the brain, compared to non-carriers; however, other studies demonstrated no difference.

Further confirmation of a link between PD and the GBA gene arose from a 2020 genome-wide association study. Analysis of the alpha-synuclein gene, SNCA, identified a polymorphism that was associated with an increased likelihood of developing PD in GBA carriers. The same polymorphism was associated with accelerated motor decline in GBA-PD patients, suggesting a role for alpha-synuclein in disease severity. Interestingly, when brain samples from GBA mutation carriers who had a diagnosis of PD or Lewy body dementia were analysed, GCase was present in 32–90% of Lewy bodies, compared to non-mutation carriers, where less than 10% of Lewy bodies were GCase-positive. This suggests there may be a direct interaction occurring between GCase and alpha-synuclein.

5. Mutations in the GBA Gene

To date, approximately 300 pathogenic mutations in the GBA gene have been identified. These include substitutions, insertions, deletions and complex alleles. The most prevalent mutations are missense mutations, with the point mutations c.1226A > G (N370S) and c.1448T > C (L444P) most commonly associated with GD. Some GBA mutations arise from genetic rearrangements and deletions between the functional GBA gene and a highly homologous pseudogene (GBAP).

The degree of PD pathogenicity associated with each individual GBA mutation differs. Some mutations have been stratified into mild or severe. The severity of a GBA mutation is based upon the phenotype it presents when homozygous in those with GD. It is thought that mutation severity inversely correlates with GCase activity. Severe mutations are associated with an earlier age of onset and a greater odds ratio for developing PD compared to mild mutations and may be associated with a higher burden of symptoms, greater cognitive decline and risk of dementia. PD odds ratios range between 2.84 and 4.94 for mild mutations and 9.92 and 21.29 for severe GBA mutations.

The proximity of mutations to the active site is not a reliable predictor of disease severity as disease-causing mutations have been found throughout the entire protein (Figure 1). For example, the L444P mutation is generally a severe GBA mutation although it is located far from the active site. Interestingly, some GBA variants, such as E326K, are referred to as risk variants due to the observation that they do not present any clinical features of GD when homozygous, yet increase the risk for developing PD in both homozygous and heterozygous forms. Along with the severe L444P and mild N370S mutations, the E326K variant is believed to be one of the most prevalent GBA variants in PD patients, and patients harbouring this variant have been associated with a severe PD phenotype. This observation suggests that the mechanisms underlying GBA-PD may be separate from those leading to GD. A summary of the effects of the N370S, L444P and E326K mutations can be found in Table 1.

6. GBA Activity and PD

Mutations in the GBA gene affect GCase activity differently, with some mutations causing abolition of enzyme activity and others retaining some residual activity. Several mutations occur in and around the active site, which commonly cause GD, and ultimately destabilise the active site to affect GCase activity.

In GD, GCase activity is normally 10–20% of controls, whereas carriers can retain up to 50%. In human brains from GBA-PD patients, GCase activity is specifically reduced, with the greatest reduction observed in the SNpc. A reduction in enzyme activity has also been observed in dried blood spots from patients harbouring GBA mutations, with heterozygotes retaining more activity compared to homozygotes and compound heterozygotes. To date, there is no evidence of a correlation between GCase activity and GBA-PD risk.

A link between GCase activity and alpha-synuclein may underlie the relationship between GBA mutations and PD. An inverse correlation has been observed between GCase activity and alpha-synuclein accumulation in GBA-PD and sporadic PD brains. The same has been observed in GCase-deficient mouse, fly and cell models. Recently, midbrain-like organoids deficient in GCase and over-expressing wild-type alpha-synuclein accumulated Lewy body-like pathology, which was absent in organoids with GCase deficiency or SNCA triplication alone, suggesting that impaired GCase function promotes alpha-synuclein pathology.

Further supporting evidence for a loss-of-function relationship between GCase and alpha-synuclein arises from the observation that enhancing GCase activity can rescue alpha-synuclein pathology. It has been proposed that there may be a reciprocal relationship between GCase and alpha-synuclein as over-expression of alpha-synuclein results in decreased GCase activity in cell models. One study also suggested that pathogenic fibrillar forms of alpha-synuclein may induce a time-dependent reduction in GCase activity in primary neurons and transgenic mice treated with the GCase inhibitor conduritol-b-epoxide (CBE).

Although these studies provide a link between reduced GCase activity and alpha-synuclein pathology, other studies in cell and animal models have failed to demonstrate such a link. In iPSC-derived dopamine neurons carrying homozygote or heterozygote GBA mutations, alpha-synuclein pathology was similar, although GCase activity was significantly lower in homozygotes. Interestingly, in primary neurons and transgenic mouse models treated with CBE, GCase inhibition did not lead to an increase in total alpha-synuclein or the formation of alpha-synuclein pathology but did enhance pre-existing alpha-synuclein pathology, leading to an elevation in pathogenic phosphorylated alpha-synuclein (p-S129-alpha-synuclein). This finding was not neuron-specific.

Considering that GBA mutation carriers are as likely to develop PD as homozygotes even though they retain more activity, and that most GD patients do not develop PD even though GCase activity is very low, it seems likely that loss of activity is not solely responsible for PD onset.

In addition to GBA-PD, GCase activity has been reported to be reduced in brains of sporadic PD patients. A similar reduction has also been observed in the CSF, dried blood spots and monocytes of PD patients with and without GBA mutations. The reports linking a reduction in GCase activity and protein level to sporadic PD confirm the relevance of GCase and its function to the wider PD population.

7. Mechanism Underlying GBA-PD

An overview of the possible mechanisms underlying the link between GCase, alpha-synuclein and PD can be found in Figure 2.

8. ER Stress

Mutations in the GBA gene may lead to the production of a misfolded protein, which can be retained in the ER to induce ER stress. There is mounting evidence from cell and animal models pointing towards a gain-of-function mechanism for GBA mutations that involves ER retention and activation of the pathways associated with ER stress, including ERAD and the UPR. The extent of ER stress may correlate with disease severity. This may be due to more severe conformational changes occurring, affecting protein stability.

In human dopamine neurons and Drosophila flies harbouring the L444P and N370S mutations, the activation of ER stress pathways has been demonstrated, and in one study, this was accompanied by increased alpha-synuclein release, providing a link between ER stress and alpha-synuclein homeostasis. Inhibition of GCase activity can elicit an ER stress response in neuroblastoma cells, indicating that enzyme activity may play a role independent of the presence of a pathogenic mutated protein. This suggests that ER stress may occur due to a combination of gain-of-function and loss-of-function mechanisms.

A recent study has suggested that the initial accumulation of alpha-synuclein may cause dysfunction of the ER, leading to the accumulation of misfolded and immature GCase protein. In midbrain neurons from PD patients with SNCA triplications, the accumulation of alpha-synuclein led to ER fragmentation and compromised ER protein folding capacity. Immature, misfolded GCase protein was retained in the ER and lacked activity, likely due to the inability of the ER to activate the UPR. This may explain why GCase activity is reduced in sporadic PD and highlights the possibility of both loss-of-function and gain-of-function roles in GBA-PD.

The current literature surrounding GBA mutations and the ER suggests that early intervention to alleviate ER stress may be an attractive therapeutic avenue to explore to treat GBA-PD.

9. Autophagic-Lysosomal Pathway

Balance between the synthesis and degradation of molecules and organelles is critical for cellular homeostasis and proper cell function. This is controlled by the ALP which is the cells’ major mechanism of protein clearance and organelle turnover. There are three types of autophagic pathways including macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). There are several key acid hydrolases within the lysosome to help with degradation, including GCase, and when there is defective function, there is impaired clearance.

The proper function of the ALP is critical for the degradation of alpha-synuclein. Defective ALP has been reported in GBA-PD patient brains and neurons. Several cell and animal models of GBA deficiency demonstrate ALP dysfunction. Impaired autophagic and proteasomal pathways, as a result of GCase deficiency, have also been reported to lead to the accumulation of dysfunctional mitochondria.

Evidence points toward a correlation between defective ALP and alpha-synuclein pathology in models of GCase deficiency. Impaired ALP mechanisms are evident in GBA-deficient neurons and brains and accompanied by alpha-synuclein pathology. Furthermore, in cortical neurons from L444P/WT mice, the half-life of alpha-synuclein was increased by more than 70% compared to cells from WT/WT littermates, suggesting deficient turnover. A bidirectional loop has been proposed to explain the relationship between GBA mutations, alpha-synuclein and the lysosome, involving the accumulation of GSLs and alpha-synuclein and prevention of lysosomal trafficking of newly synthesised GCase from the ER which further exacerbates lysosomal dysfunction.

Another link between GCase, alpha-synuclein and CMA has recently been suggested, which involves the mislocalisation of mutant GCase to the surface of lysosomes. In GBA-PD human brains, half of the mutant GCase in the lysosome was present on the lysosome surface. This mislocalisation was dependent on a pentapeptide motif in GCase, which is used to target cytosolic proteins for degradation by CMA. Therefore, the binding of mutant GCase to the lysosome prevents CMA, causing the accumulation of CMA substrates including alpha-synuclein. Further analysis in GBA-PD dopamine neurons and fibroblasts confirmed defective CMA.

Mounting evidence now points toward the cell-to-cell transmission of alpha-synuclein to propagate pathology around the brain. If alpha-synuclein degradation is impaired, it may be secreted out of the neuron in an exosome-mediated pathway in an attempt to overcome its accumulation. A GCase deficiency has been shown to increase the propagation of alpha-synuclein pathology through the cell-to-cell transmission of toxic alpha-synuclein, possibly through extracellular vesicle release. In N370S dopamine neurons, this increase in alpha-synuclein secretion was coincident with ALP defects. Recently, GCase has been suggested to have a role in the secretion and spread of protein aggregates, as in GBA-deficient Drosophila flies, protein aggregation was increased through dysregulated extracellular vesicles, and wild-type GCase was able to be packaged and trafficked between cells. In another Drosophila study, knock-out of GBA resulted in autophagic defects and an abundance of proteins associated with exosome release. Further evidence arises from the analysis of wild-type and L444P/+ mouse brains following a single injection of mouse alpha-synuclein pre-formed fibrils in the striatum. Enhanced propagation of alpha-synuclein pre-formed fibrils was observed in the L444P/+ mouse brain, compared to the control, with widespread alpha-synuclein deposits throughout the brain, suggesting this mutation increases the formation and spread of alpha-synuclein pathology.

10. Lipid Homeostasis

Dysfunction of cellular lipid homeostasis may underlie PD pathology. Lipid homeostasis is necessary for synaptic plasticity and neuronal function. The pathological fibrilisation of alpha-synuclein is thought to be strongly mediated by physiological interactions between alpha-synuclein and lipids. A previous study using solution-state nuclear magnetic resonance (NMR) proposed that GCase can directly inhibit lipid-induced aggregation by binding to the C terminal of alpha-synuclein, causing its dissociation from lipids at the N terminal. The same mechanism was also shown to destabilise mature fibrils. However, it remains debatable whether the binding of lipids to alpha-synuclein promotes or prevents aggregation.

Lipid membrane fluidity is essential for the efficient binding of alpha-synuclein. If aberrant lipid homeostasis occurs, this may alter the lipid membrane composition or fluidity and the binding of alpha-synuclein, leading to subsequent neurotoxicity. Alterations in the lipid composition have been reported in PD brains, including changes in levels of fatty acids and the lipid raft content. Changes in membrane fluidity could greatly affect alpha-synuclein degradation as membrane dynamics are required for macroautophagy and CMA.

Alterations in lipid metabolism seem to play a role in GBA-PD neurodegeneration. Accumulation of GCase substrates, GlcCer and GlcSph, is a key feature in animal models of GBA deficiency. In a GBA-PD mouse model, reducing GSL levels improved cognitive symptoms. Fibroblasts from WT/L444P PD patients have also demonstrated a significant increase in GSLs compared to healthy controls and sporadic PD patients, which correlated with decreased GCase activity. Excess GSLs can alter the lipid membrane composition, leading to changes in membrane fluidity and curvature.

Currently, the presence of GSL accumulation is yet to be shown in GBA-PD brains. However, there is evidence of GlcCer and GlcSph accumulation in PD and neuropathic GD brains.

A direct link between GSL accumulation and alpha-synuclein fibrilisation has also been suggested. The accumulation of GlcCer has been shown to stabilise toxic alpha-synuclein oligomers and enhance its propagation in cell models of GBA deficiency. Lipids extracted from WT/L444P fibroblasts, but not controls, were able to accelerate the aggregation of recombinant alpha-synuclein, due to a higher content of short-chain lipids. A recent study has also demonstrated that over-expression of wild-type GCase in mouse brains reduced the accumulation of lipid-rich alpha-synuclein aggregates, providing further evidence for a role of GCase in lipid and alpha-synuclein homeostasis.

A deficiency in GCase has not only been associated with increases in GSL levels, but also with alterations in the composition of other lipid species including ceramide. In the SNpc of PD brains and brains from GD patients, the marker of lipid-induced stress, glycoprotein NMB (GPNMB), is selectively elevated. This presents further evidence for a primary role for aberrant lipid metabolism in GBA-PD degeneration.

Experimental data suggest there may be specific cell types that present a selective vulnerability to lipid alterations. Studies using human brains contain a mixture of neurons and glia, and it may be that substrate accumulation is cell-specific. This highlights the difficulty of determining lipid alterations where small changes may be difficult to detect in certain cell types. Furthermore, it could be that subtle changes in the subcellular localisation of the substrate or alterations in the distribution of species affect alpha-synuclein metabolism.

11. Mitochondrial Dysfunction

Mitochondria play a central role in energy production by oxidative phosphorylation. However, they are also heavily involved in other cellular processes including regulation of calcium homeostasis, membrane potential, apoptosis and stress response. Impairment of mitochondrial function is thought to play a key role in PD pathogenesis, and some studies have investigated the link between GCase and mitochondrial dysfunction. In GCase-deficient cells, mice and flies, mitochondrial abnormalities have been observed including oxidative stress, reduced ATP levels, reduced oxygen consumption and abnormal mitochondrial morphology. In GBA knock-out flies, these abnormalities were accompanied by an increased sensitivity to oxidative stress, lysosomal dysfunction and impaired autophagic flux.

Although the cause of mitochondrial dysfunction in PD remains unclear, impairment of the ALP may contribute. Defective ALP-mediated clearance of damaged mitochondria has been demonstrated in iPSC-derived dopamine neurons from GBA mutation carriers and Drosophila fly models. Furthermore, it has also been proposed that the pathogenic accumulation of alpha-synuclein can render dopamine neurons more susceptible to mitochondrial dysfunction induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an L444P/WT mouse model, providing a link between GCase, alpha-synuclein and mitochondrial function.

12. Neuroinflammation

Neuroinflammation may play an important role in the pathogenesis of PD. High concentrations of inflammatory markers have been observed in the serum of GD patients, highlighting a link between GBA mutations and inflammation. In animal models of GCase deficiency, there is considerable neuroinflammation including activation of microglia, upregulation of inflammatory cytokines and higher levels of immune markers in the plasma.

It may be that neuroinflammation arises as a result of GlcCer, GlcSph or alpha-synuclein accumulation within neurons, which can activate microglia. Alpha-synuclein may be secreted and able to bind directly to Toll-like receptors on the microglia and activate them, resulting in neuroinflammation. If an increase in the extracellular release of alpha-synuclein occurs, possibly due to a GBA mutation, alpha-synuclein can be taken up into the microglia and astrocytes for degradation; however, if these cells are GCase-deficient, then alpha-synuclein degradation may be defective through improper ALP function and thus contribute to the spread of alpha-synuclein pathology.

13. GCase as a Therapeutic Target

The link between the GBA gene and PD has now opened a new avenue for therapies, with GCase as a novel target. Although dopaminergic therapy and deep brain stimulation (DBS) may be efficacious in alleviating symptoms in GBA-PD patients, research is ongoing to develop GCase-targeted therapies to prevent neurodegeneration (Table 2).

Current promising therapies for GD include ERT and SRT. ERT works by administering active, recombinant GCase protein to the cells to increase GCase protein and activity. SRT works to reduce the accumulation of GCase substrates by inhibiting the biosynthesis of GlcCer and GlcSph. Both have shown great efficacy in improving the visceral symptoms of GD but are unable to cross the blood–brain barrier and thus are ineffective in treating neuronopathic symptoms of GD or GBA-PD.

Alternative methods to improve the delivery of the recombinant GCase enzyme for ERT are being investigated. These involve ligating a peptide to the GCase enzyme to enhance its ability to cross the blood–brain barrier. The Tat peptide, derived from the transactivator protein of HIV, has been used as Tat-linked cargo proteins have demonstrated increased uptake by micropinocytosis, independent of cell surface receptors. Similarly, peptides derived from Rabies virus have been shown to be promising in improving the delivery of brain-targeted proteins. When GCase is tagged with such peptides, studies have demonstrated enhanced delivery into neuronal cells compared to untagged GCase, with the ability to reduced lipid accumulation. Preclinical research is also ongoing for the transport-vehicle-modified recombinant GCase enzyme (ETV:GBA), which is a transport vehicle platform technology to actively transport enzymes across the blood–brain barrier through receptor-mediated transcytosis. Further studies are required to investigate the efficacy of these methods in treating GBA-PD.

Similar to ERT, novel brain-penetrant SRTs are currently under investigation to treat GBA-PD. The inhibition of GSL synthesis may reduce alpha-synuclein aggregation and neuronal cell death. Treatment with the SRT miglustat is able to reduce GSL accumulation in dopamine neurons from GBA-PD patients, and when coupled with GCase over-expression, this therapy was able to protect against alpha-synuclein toxicity; however, its efficacy is limited as it cannot cross the blood–brain barrier. A potent, brain-penetrant inhibitor of GlcCer synthase, GZ667161 (venglustat), has demonstrated efficacy in reducing alpha-synuclein and GSL accumulation, in addition to ameliorating cognitive dysfunction in a GD synucleinopathy mouse model. Although the initial results from a phase I study of venglustat demonstrated target engagement with no serious adverse effects (ClinicalTrials.gov Identifier: NCT01674036 and NCT01710826), the recent phase II clinical trial showed no benefit and was associated with a decline in motor function in GBA-PD (ClinicalTrials.gov Identifier: NCT02906020), suggesting that this drug is ineffective in treating GBA-PD. Further development of brain-penetrant SRTs remains a strategy for PD disease modification.

Gene therapy is another method being explored to deliver active, recombinant GCase protein to the brain. Adeno-associated virus (AAV) is a viral vector used for gene delivery into the brain and can deliver to the host cell nucleus without integration into the host genome. AAV-mediated expression of human recombinant GCase in the hippocampus of a pre-symptomatic mouse model of GD has been shown to be effective in reducing alpha-synuclein pathology. Further studies in a symptomatic GD mouse model and in a transgenic mouse model over-expressing alpha-synuclein showed that when virus-encoding human recombinant GCase was injected into the CNS, there was increased GCase expression and activity, which led to a reduction in the levels of GSLs and alpha-synuclein aggregates. The same was exhibited by an AAV-mediated increase in GCase levels in rodent PD models. In a recent study, an injection of viral vectors containing recombinant GCase was sufficient to enhance GCase activity, reduce the alpha-synuclein burden and prevent neuronal death in the SNpc in a synucleinopathy mouse model. Gene therapy targeting the GBA gene using an AAV-9 vector (PR001A) for the treatment of GBA-PD is currently in phase I clinical trials (ClinicalTrials.gov Identifier: NCT04127578). The compound is also being tested in infants with type 2 GD (ClinicalTrials.gov Identifier: NCT04411654).

Other promising GCase-targeted therapies undergoing preclinical and clinical trials include molecular chaperones. Since they have the potential to penetrate the blood–brain barrier effectively, small molecular chaperones of GCase have gained much focus recently for the treatment of PD. These compounds can bind misfolded, mutant GCase in the ER, facilitate the correct folding and increase activity and stability whilst aiding in trafficking to the lysosome. Two types of molecular chaperones exist: inhibitory chaperones, which bind to the active site of the GCase protein, and noninhibitory chaperones, which bind to an alternate site of the GCase protein.

A number of inhibitory small molecule chaperone candidates have been identified as potential treatments for GBA-PD, including repurposed drugs such as ambroxol and isofagomine. In fibroblasts and neurons with GBA mutations, such chaperones have demonstrated efficacy in increasing the GCase protein level and activity and aided in the trafficking of mutant GCase to the lysosome. Both ambroxol and isofagomine have been shown to successfully reduce ER stress and improve symptoms in GBA-mutant Drosophila flies. Challenges arise when using inhibitory compounds, as GCase must out-compete the inhibitors in order to gain access to the enzyme active site at the lysosome. This competition requires the drug dosage to be carefully optimised to ensure the inhibitors act solely as a chaperone to successfully refold and deliver GCase to the lysosome, and not as an inhibitor of GCase.

Ambroxol is a pH-dependent inhibitory chaperone of GCase with the ability not only to increase GCase activity, but also to reduce alpha-synuclein pathology. Ambroxol exhibits its maximal inhibitory activity at the neutral pH of the ER, and when in the acidic environment of the lysosome, it exhibits nondetectable inhibition. Oral administration of ambroxol has demonstrated increased GCase activity in the brain of mice and non-human primates. Trials investigating the safety and efficacy of ambroxol in humans are now underway. In type 1 GD patients, ambroxol was safely tolerated and exerted a positive effect on GCase (ClinicalTrials.gov Identifier: NCT03950050). In a recent single-centre, open-label, noncontrolled clinical trial with GBA-PD and sporadic PD patients treated with increasing doses of the drug, ambroxol was well tolerated and safe. It was found that ambroxol successfully crosses the blood–brain barrier and enters the CSF where it alters GCase activity and protein levels (ClinicalTrials.gov Identifier: NCT02941822). This suggests that there is successful target engagement of ambroxol with GCase. The next step is to perform a larger trial and study the efficacy of ambroxol in treating GBA-PD and idiopathic PD, and this study is currently planned to begin recruitment in late 2022.

To overcome the challenges associated with inhibitory chaperones, there is significant interest in the development of novel noninhibitory small molecular chaperones for the treatment of PD. Two noninhibitory small molecular modulators of GCase have been identified, namely, NCGC758 and NCGC607. Treatment of iPSC-derived dopaminergic neurons from GBA-PD patients with these compounds has demonstrated increased lysosomal trafficking of GCase coupled with reduced GSL and alpha-synuclein accumulation. Another noninhibitory small molecule is the GCase activator LTI-291, which has undergone a phase I clinical trial and demonstrated safety and tolerability in participants, with the ability to penetrate the brain (Trialregister.nl ID: NTR7299).

An exciting avenue currently being explored is the use of small molecules to modulate GCase via GCase-independent pathways. One example of this is RTB101, which is an inhibitor of rapamycin complex 1 (TORC1). The role of mTORC1 is to regulate autophagy, and inhibition has been shown to increase autophagy and prevent neuronal cell death in a mouse model of Alzheimer’s disease and improve motor function in parkinsonism rats. GCase can also be manipulated by the modulation of misfolded GCase through small molecules targeting proteins that are involved in the refolding of mutant GCase in times of stress. Such compounds include histone deacetylase inhibitors (HDACis), which lead to aberrant acetylation of chaperones such as heat shock protein (Hsp) 90, preventing Hsp90 binding to GCase and the subsequent ubiquitination and proteasomal degradation of GCase, ultimately leading to increased GCase activity in GD fibroblast lines. Additionally, compounds such as arimoclomol can activate Hsp70 to enhance the correct folding and localisation of mutated GCase and have been shown to increase GCase activity in L444P fibroblasts. Future studies may involve identifying GCase-independent pathways that are able to be manipulated to enhance GCase trafficking and activity, in order to slow down disease progression in PD and alpha-synuclein models.

Significant progress has been made in the development of brain-penetrant GCase-targeted therapies; however, it still remains unclear which therapeutic strategy is best suited to treat GBA-PD in terms of efficacy, safety and reproducibility. A key challenge is the limited understanding of the precise pathways by which individual GBA mutations increase the risk of developing PD, and thus there may be vast differences between the effectiveness of therapeutic strategies between patients.

14. Conclusions

The discovery of the link between GBA mutations and PD has provided invaluable insight into the pathogenesis of the disease and novel perspectives for GCase-targeted therapies to prevent neurodegeneration. There is growing evidence highlighting the involvement of pathways including the ALP, lipid metabolism, the ER, mitochondria and neuroinflammation in GBA-PD, and there seems to be a reciprocal relationship between GCase and alpha-synuclein. However, much is yet to be understood regarding the molecular basis that underlies the increased risk for PD in GBA mutation carriers, why different mutations are associated with differential risks and why gain- or loss-of-function pathways are associated with individual mutations. Further, it is important to understand why some GBA mutation carriers develop PD, while some do not. Improving our understanding of how GBA mutations influence the predisposition to PD is imperative to facilitate the development of novel and efficacious therapeutics to halt disease progression.

References 234

  1. 1.

    Braak H. Neuropathological Staging of Brain Pathology in Sporadic Parkinson’s disease: Separating the Wheat from the Chaff. J. Park. Dis. 2017;7:S71-S85.

    Not in our library10.3233/jpd-179001

  2. 2.

    Turpin J.C., Dubois G., Brice A., Masson M., Nadaud M.C., Boutry J.M., Schram A.W., Tager J.M., Baumann N. Parkinsonian Symptomatology in a Patient with Type I (Adult) Gaucher’s Disease. 1988;103-105.

    Not in our library

  3. 3.

    McKeran R.O., Bradbury P., Taylor D., Stern G. Neurological involvement in type 1 (adult) Gaucher’s disease. J. Neurol. Neurosurg. Psychiatry. 1985;48:172-175.

    Not in our library10.1136/jnnp.48.2.172

  4. 4.

    Sidransky E., Lopez G. The link between the GBA gene and parkinsonism. Lancet Neurol. 2012;11:986-998.

    Not in our library10.1016/s1474-4422(12)70190-4

  5. 5.

    Bultron G., Kacena K., Pearson D., Boxer M., Yang R., Sathe S., Pastores G., Mistry P.K. The risk of Parkinson’s disease in type 1 Gaucher disease. J. Inherit. Metab. Dis. 2010;33:167-173.

    Not in our library10.1007/s10545-010-9055-0

  6. 6.

    Gan-Or Z., Amshalom I., Kilarski L.L., Bar-Shira A., Gana-Weisz M., Mirelman A., Marder K., Bressman S., Giladi N., Orr-Urtreger A. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology. 2015;84:880-887.

    Not in our library10.1212/wnl.0000000000001315

  7. 7.

    Sidransky E., Nalls M.A., Aasly J.O., Aharon-Peretz J., Annesi G., Barbosa E.R., Bar-Shira A., Berg D., Bras J., Brice A., et al. Multi-center analysis of glucocerebrosidase mutations in Parkinson disease. N. Engl. J. Med. 2009;361:1651-1661.

    Not in our library10.1056/nejmoa0901281

  8. 8.

    Tayebi N., Callahan M., Madike V., Stubblefield B.K., Orvisky E., Krasnewich D., Fillano J.J., Sidransky E. Gaucher disease and parkinsonism: A phenotypic and genotypic characterization. Mol. Genet. Metab. 2001;73:313-321.

    Not in our library10.1006/mgme.2001.3201

  9. 9.

    Hruska K.S., LaMarca M.E., Scott C.R., Sidransky E. Gaucher disease: Mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum. Mutat. 2008;29:567-583.

    Not in our library10.1002/humu.20676

  10. 10.

    Beutler E., Beutler L., West C. Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher disease. J. Lab. Clin. Med. 2004;144:65-68.

    Not in our library10.1016/j.lab.2004.03.013

  11. 11.

    Gegg M.E., Schapira A.H.V. The role of glucocerebrosidase in Parkinson disease pathogenesis. FEBS J. 2018;285:3591-3603.

    Not in our library10.1111/febs.14393

  12. 12.

    Balestrino R., Schapira A.H.V. Parkinson disease. Eur. J. Neurol. 2020;27:27-42.

    Not in our library10.1111/ene.14108

  13. 13.

    Schapira A.H.V., Chaudhuri K.R., Jenner P. Non-motor features of Parkinson disease. Nat. Rev. Neurosci. 2017;18:435-450.

    Not in our library10.1038/nrn.2017.62

  14. 14.

    Marsden C.D. Parkinson’s disease. Lancet. 1990;335:948-952.

    Not in our library10.1016/0140-6736(90)91006-v

  15. 15.

    Spillantini M.G., Schmidt M.L., Lee V.M., Trojanowski J.Q., Jakes R., Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839-840.

    Not in our library10.1038/42166

  16. 16.

    Wakabayashi K., Tanji K., Odagiri S., Miki Y., Mori F., Takahashi H. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol. Neurobiol. 2013;47:495-508.

    Not in our library10.1007/s12035-012-8280-y

  17. 17.

    Shahmoradian S.H., Lewis A.J., Genoud C., Hench J., Moors T.E., Navarro P.P., Castano-Diez D., Schweighauser G., Graff-Meyer A., Goldie K.N., et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 2019;22:1099-1109.

    Not in our library10.1038/s41593-019-0423-2

  18. 18.

    Braak H., Tredici K.D., Rüb U., de Vos R.A.I., Jansen Steur E.N.H., Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging. 2003;24:197-211.

    Not in our library10.1016/s0197-4580(02)00065-9

  19. 19.

    Ono K. The Oligomer Hypothesis in α-Synucleinopathy. Neurochem. Res. 2017;42:3362-3371.

    Not in our library10.1007/s11064-017-2382-x

  20. 20.

    Spillantini M.G., Crowther R.A., Jakes R., Cairns N.J., Lantos P.L., Goedert M. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 1998;251:205-208.

    Not in our library10.1016/s0304-3940(98)00504-7

  21. 21.

    Alam P., Bousset L., Melki R., Otzen D.E. α-Synuclein oligomers and fibrils: A spectrum of species, a spectrum of toxicities. J. Neurochem. 2019;150:522-534.

    Not in our library10.1111/jnc.14808

  22. 22.

    Cuervo A.M., Stefanis L., Fredenburg R., Lansbury P.T., Sulzer D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science. 2004;305:1292-1295.

    Not in our library10.1126/science.1101738

  23. 23.

    Martinez-Vicente M., Cuervo A.M. Autophagy and neurodegeneration: When the cleaning crew goes on strike. Lancet Neurol. 2007;6:352-361.

    Not in our library10.1016/s1474-4422(07)70076-5

  24. 24.

    Alvarez-Erviti L., Rodriguez-Oroz M.C., Cooper J.M., Caballero C., Ferrer I., Obeso J.A., Schapira A.H. Chaperone-mediated autophagy markers in Parkinson disease brains. Arch. Neurol. 2010;67:1464-1472.

    Not in our library10.1001/archneurol.2010.198

  25. 25.

    Dehay B., Bove J., Rodriguez-Muela N., Perier C., Recasens A., Boya P., Vila M. Pathogenic lysosomal depletion in Parkinson’s disease. J. Neurosci. 2010;30:12535-12544.

    Not in our library10.1523/jneurosci.1920-10.2010

  26. 26.

    Li J.Y., Englund E., Holton J.L., Soulet D., Hagell P., Lees A.J., Lashley T., Quinn N.P., Rehncrona S., Bjorklund A., et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 2008;14:501-503.

    Not in our library10.1038/nm1746

  27. 27.

    Kordower J.H., Chu Y., Hauser R.A., Freeman T.B., Olanow C.W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 2008;14:504-506.

    Not in our library10.1038/nm1747

  28. 28.

    Reczek D., Schwake M., Schröder J., Hughes H., Blanz J., Jin X., Brondyk W., Van Patten S., Edmunds T., Saftig P. LIMP-2 Is a Receptor for Lysosomal Mannose-6-Phosphate-Independent Targeting of β-Glucocerebrosidase. Cell. 2007;131:770-783.

    Not in our library10.1016/j.cell.2007.10.018

  29. 29.

    Grabowski G.A., Gatt S., Horowitz M. Acid beta-glucosidase: Enzymology and molecular biology of Gaucher disease. Crit Rev. Biochem. Mol. Biol. 1990;25:385-414.

    Not in our library10.3109/10409239009090616

  30. 30.

    Bergmann J.E., Grabowski G.A. Posttranslational processing of human lysosomal acid beta-glucosidase: A continuum of defects in Gaucher disease type 1 and type 2 fibroblasts. Am. J. Hum. Genet. 1989;44:741-750.

    Not in our library

  31. 31.

    Lieberman R.L. A Guided Tour of the Structural Biology of Gaucher Disease: Acid-beta-Glucosidase and Saposin C. Enzym. Res. 2011;2011:973231.

    Not in our library10.4061/2011/973231

  32. 32.

    Dvir H., Harel M., McCarthy A.A., Toker L., Silman I., Futerman A.H., Sussman J.L. X-ray structure of human acid-beta-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 2003;4:704-709.

    Not in our library10.1038/sj.embor.embor873

  33. 33.

    Horowitz M., Pasmanik-Chor M., Borochowitz Z., Falik-Zaccai T., Heldmann K., Carmi R., Parvari R., Beit-Or H., Goldman B., Peleg L., et al. Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population. Hum. Mutat. 1998;12:240-244.

    Not in our library10.1002/(sici)1098-1004(1998)12:4<240::aid-humu4>3.0.co;2-j

  34. 34.

    Charrow J., Andersson H.C., Kaplan P., Kolodny E.H., Mistry P., Pastores G., Rosenbloom B.E., Scott C.R., Wappner R.S., Weinreb N.J., et al. The gaucher registry: Demographics and disease characteristics of 1698 patients with gaucher disease. Arch. Intern. Med. 2000;160:2835-2843.

    Not in our library10.1001/archinte.160.18.2835

  35. 35.

    Grabowski G.A. Phenotype, diagnosis, and treatment of Gaucher’s disease. Lancet. 2008;372:1263-1271.

    Not in our library10.1016/s0140-6736(08)61522-6

  36. 36.

    Beavan M., McNeill A., Proukakis C., Hughes D.A., Mehta A., Schapira A.H. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol. 2015;72:201-208.

    Not in our library10.1001/jamaneurol.2014.2950

  37. 37.

    Wong K., Sidransky E., Verma A., Mixon T., Sandberg G.D., Wakefield L.K., Morrison A., Lwin A., Colegial C., Allman J.M., et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol. Genet. Metab. 2004;82:192-207.

    Not in our library10.1016/j.ymgme.2004.04.011

  38. 38.
    A characterization of Gaucher iPS-derived astrocytes: Potential implications for Parkinson's disease · 2020
    Not checked
  39. 39.

    Maegawa G.H.B., Tropak M.B., Buttner J.D., Rigat B.A., Fuller M., Pandit D., Tang L.I., Kornhaber G.J., Hamuro Y., Clarke J.T.R., et al. Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease. J. Biol. Chem. 2009;284:23502-23516.

    Not in our library10.1074/jbc.m109.012393

  40. 40.

    Mata I.F., Samii A., Schneer S.H., Roberts J.W., Griffith A., Leis B.C., Schellenberg G.D., Sidransky E., Bird T.D., Leverenz J.B., et al. Glucocerebrosidase gene mutations: A risk factor for Lewy body disorders. Arch. Neurol. 2008;65:379-382.

    Not in our library10.1001/archneurol.2007.68

  41. 41.

    Alcalay R.N., Dinur T., Quinn T., Sakanaka K., Levy O., Waters C., Fahn S., Dorovski T., Chung W.K., Pauciulo M., et al. Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. JAMA Neurol. 2014;71:752-757.

    Not in our library10.1001/jamaneurol.2014.313

  42. 42.

    Anheim M., Elbaz A., Lesage S., Durr A., Condroyer C., Viallet F., Pollak P., Bonaiti B., Bonaiti-Pellie C., Brice A., et al. Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers. Neurology. 2012;78:417-420.

    Not in our library10.1212/wnl.0b013e318245f476

  43. 43.

    McNeill A., Duran R., Hughes D.A., Mehta A., Schapira A.H. A clinical and family history study of Parkinson’s disease in heterozygous glucocerebrosidase mutation carriers. J. Neurol. Neurosurg. Psychiatry. 2012;83:853-854.

    Not in our library10.1136/jnnp-2012-302402

  44. 44.

    Lwin A., Orvisky E., Goker-Alpan O., LaMarca M.E., Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol. Genet. Metab. 2004;81:70-73.

    Not in our library10.1016/j.ymgme.2003.11.004

  45. 45.
    The relationship between glucocerebrosidase mutations and Parkinson disease · 2016
    No notice
  46. 46.

    Neumann J., Bras J., Deas E., O’Sullivan S.S., Parkkinen L., Lachmann R.H., Li A., Holton J., Guerreiro R., Paudel R., et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132:1783-1794.

    Not in our library10.1093/brain/awp044

  47. 47.

    Lesage S., Anheim M., Condroyer C., Pollak P., Durif F., Dupuits C., Viallet F., Lohmann E., Corvol J.C., Honore A., et al. Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum. Mol. Genet. 2011;20:202-210.

    Not in our library10.1093/hmg/ddq454

  48. 48.

    Higgins A.L., Toffoli M., Mullin S., Lee C.Y., Koletsi S., Avenali M., Blandini F., Schapira A.H. The remote assessment of parkinsonism supporting the ongoing development of interventions in Gaucher disease. Neurodegener. Dis. Manag. 2021;11:451-458.

    Not in our library10.2217/nmt-2021-0032

  49. 49.

    Goker-Alpan O., Giasson B.I., Eblan M.J., Nguyen J., Hurtig H.I., Lee V.M.Y., Trojanowski J.Q., Sidransky E. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology. 2006;67:908-910.

    Not in our library10.1212/01.wnl.0000230215.41296.18

  50. 50.

    Zhang Y., Sun Q.Y., Zhao Y.W., Shu L., Guo J.F., Xu Q., Yan X.X., Tang B.S. Effect of GBA Mutations on Phenotype of Parkinson’s Disease: A Study on Chinese Population and a Meta-Analysis. Parkinson’s Dis. 2015;2015:916971.

    Not in our library10.1155/2015/916971

  51. 51.

    Gan-Or Z., Bar-Shira A., Mirelman A., Gurevich T., Kedmi M., Giladi N., Orr-Urtreger A. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics. 2010;11:121-125.

    Not in our library10.1007/s10048-009-0198-9

  52. 52.

    Gan-Or Z., Giladi N., Rozovski U., Shifrin C., Rosner S., Gurevich T., Bar-Shira A., Orr-Urtreger A. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008;70:2277-2283.

    Not in our library10.1212/01.wnl.0000304039.11891.29

  53. 53.
    Features of GBA -associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study · 2018
    No notice
  54. 54.

    Goker-Alpan O., Lopez G., Vithayathil J., Davis J., Hallett M., Sidransky E. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch. Neurol. 2008;65:1353-1357.

    Not in our library10.1001/archneur.65.10.1353

  55. 55.

    Brockmann K., Srulijes K., Pflederer S., Hauser A.K., Schulte C., Maetzler W., Gasser T., Berg D. GBA-associated Parkinson’s disease: Reduced survival and more rapid progression in a prospective longitudinal study. Mov. Disord. Off. J. Mov. Disord. Soc. 2015;30:407-411.

    Not in our library10.1002/mds.26071

  56. 56.

    Winder-Rhodes S.E., Evans J.R., Ban M., Mason S.L., Williams-Gray C.H., Foltynie T., Duran R., Mencacci N.E., Sawcer S.J., Barker R.A. Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain. 2013;136:392-399.

    Not in our library10.1093/brain/aws318

  57. 57.

    Petrucci S., Ginevrino M., Trezzi I., Monfrini E., Ricciardi L., Albanese A., Avenali M., Barone P., Bentivoglio A.R., Bonifati V., et al. GBA-Related Parkinson’s Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort. Mov. Disord. 2020;35:2106-2111.

    Not in our library10.1002/mds.28195

  58. 58.

    Alcalay R.N., Caccappolo E., Mejia-Santana H., Tang M., Rosado L., Orbe Reilly M., Ruiz D., Ross B., Verbitsky M., Kisselev S., et al. Cognitive performance of GBA mutation carriers with early-onset PD: The CORE-PD study. Neurology. 2012;78:1434-1440.

    Not in our library10.1212/wnl.0b013e318253d54b

  59. 59.

    Brockmann K., Srulijes K., Hauser A.K., Schulte C., Csoti I., Gasser T., Berg D. GBA-associated PD presents with nonmotor characteristics. Neurology. 2011;77:276-280.

    Not in our library10.1212/wnl.0b013e318225ab77

  60. 60.

    Westbroek W., Gustafson A.M., Sidransky E. Exploring the link between glucocerebrosidase mutations and parkinsonism. Trends Mol. Med. 2011;17:485-493.

    Not in our library10.1016/j.molmed.2011.05.003

  61. 61.

    Choi J.H., Stubblefield B., Cookson M.R., Goldin E., Velayati A., Tayebi N., Sidransky E. Aggregation of α-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol. Genet. Metab. 2011;104:185-188.

    Not in our library10.1016/j.ymgme.2011.06.008

  62. 62.

    Tayebi N., Walker J., Stubblefield B., Orvisky E., LaMarca M.E., Wong K., Rosenbaum H., Schiffmann R., Bembi B., Sidransky E. Gaucher disease with parkinsonian manifestations: Does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol. Genet. Metab. 2003;79:104-109.

    Not in our library10.1016/s1096-7192(03)00071-4

  63. 63.

    Nishioka K., Ross O.A., Vilarino-Guell C., Cobb S.A., Kachergus J.M., Mann D.M., Snowden J., Richardson A.M., Neary D., Robinson C.A., et al. Glucocerebrosidase mutations in diffuse Lewy body disease. Parkinsonism Relat. Disord. 2011;17:55-57.

    Not in our library10.1016/j.parkreldis.2010.09.009

  64. 64.

    Parkkinen L., Neumann J., O’Sullivan S.S., Holton J.L., Revesz T., Hardy J., Lees A.J. Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson’s disease. Mol. Genet. Metab. 2011;103:410-412.

    Not in our library10.1016/j.ymgme.2011.04.015

  65. 65.

    Blauwendraat C., Reed X., Krohn L., Heilbron K., Bandres-Ciga S., Tan M., Gibbs J.R., Hernandez D.G., Kumaran R., Langston R., et al. Genetic modifiers of risk and age at onset in GBA associated Parkinson’s disease and Lewy body dementia. Brain. 2020;143:234-248.

    Not in our library10.1093/brain/awz350

  66. 66.

    Stoker T.B., Camacho M., Winder-Rhodes S., Liu G., Scherzer C.R., Foltynie T., Barker R.A., Williams-Gray C.H. A common polymorphism in SNCA is associated with accelerated motor decline in GBA-Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry. 2020;91:673-674.

    Not in our library10.1136/jnnp-2019-322210

  67. 67.

    Goker-Alpan O., Stubblefield B.K., Giasson B.I., Sidransky E. Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. Acta Neuropathol. 2010;120:641-649.

    Not in our library10.1007/s00401-010-0741-7

  68. 68.

    Dandana A., Ben Khelifa S., Chahed H., Miled A., Ferchichi S. Gaucher Disease: Clinical, Biological and Therapeutic Aspects. Pathobiology. 2016;83:13-23.

    Not in our library10.1159/000440865

  69. 69.

    Winfield S.L., Tayebi N., Martin B.M., Ginns E.I., Sidransky E. Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: Implications for Gaucher disease. Genome Res. 1997;7:1020-1026.

    Not in our library10.1101/gr.7.10.1020

  70. 70.

    Huh Y.E., Chiang M.S.R., Locascio J.J., Liao Z., Liu G., Choudhury K., Kuras Y.I., Tuncali I., Videnovic A., Hunt A.L., et al. Beta-Glucocerebrosidase activity in GBA-linked Parkinson disease: The type of mutation matters. Neurology. 2020;95:e685-e696.

    Not in our library10.1212/wnl.0000000000009989

  71. 71.

    Cilia R., Tunesi S., Marotta G., Cereda E., Siri C., Tesei S., Zecchinelli A.L., Canesi M., Mariani C.B., Meucci N., et al. Survival and dementia in GBA-associated Parkinson’s disease: The mutation matters. Ann. Neurol. 2016;80:662-673.

    Not in our library10.1002/ana.24777

  72. 72.

    Smith L., Mullin S., Schapira A.H.V. Insights into the structural biology of Gaucher disease. Exp. Neurol. 2017;298:180-190.

    Not in our library10.1016/j.expneurol.2017.09.010

  73. 73.

    Duran R., Mencacci N.E., Angeli A.V., Shoai M., Deas E., Houlden H., Mehta A., Hughes D., Cox T.M., Deegan P., et al. The glucocerobrosidase E326K variant predisposes to Parkinson’s disease, but does not cause Gaucher’s disease. Mov. Disord. 2013;28:232-236.

    Not in our library10.1002/mds.25248

  74. 74.

    Chabas A., Gort L., Diaz-Font A., Montfort M., Santamaria R., Cidras M., Grinberg D., Vilageliu L. Perinatal lethal phenotype with generalized ichthyosis in a type 2 Gaucher disease patient with the [L444P;E326K]/P182L genotype: Effect of the E326K change in neonatal and classic forms of the disease. Blood Cells Mol. Dis. 2005;35:253-258.

    Not in our library10.1016/j.bcmd.2005.04.007

  75. 75.

    Liou B., Grabowski G.A. Is E326K glucocerebrosidase a polymorphic or pathological variant? Mol. Genet. Metab. 2012;105:528-529.

    Not in our library10.1016/j.ymgme.2011.12.002

  76. 76.

    Berge-Seidl V., Pihlstrøm L., Maple-Grødem J., Forsgren L., Linder J., Larsen J.P., Tysnes O.-B., Toft M. The GBA variant E326K is associated with Parkinson’s disease and explains a genome-wide association signal. Neurosci. Lett. 2017;658:48-52.

    Not in our library10.1016/j.neulet.2017.08.040

  77. 77.

    den Heijer J.M., Cullen V.C., Quadri M., Schmitz A., Hilt D.C., Lansbury P., Berendse H.W., van de Berg W.D.J., de Bie R.M.A., Boertien J.M., et al. A Large-Scale Full GBA1 Gene Screening in Parkinson’s Disease in the Netherlands. Mov. Disord. 2020;35:1667-1674.

    Not in our library10.1002/mds.28112

  78. 78.

    Ruskey J.A., Greenbaum L., Roncière L., Alam A., Spiegelman D., Liong C., Levy O.A., Waters C., Fahn S., Marder K.S., et al. Increased yield of full GBA sequencing in Ashkenazi Jews with Parkinson’s disease. Eur. J. Med. Genet. 2019;62:65-69.

    Not in our library10.1016/j.ejmg.2018.05.005

  79. 79.

    Davis M.Y., Johnson C.O., Leverenz J.B., Weintraub D., Trojanowski J.Q., Chen-Plotkin A., Van Deerlin V.M., Quinn J.F., Chung K.A., Peterson-Hiller A.L., et al. Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol. 2016;73:1217-1224.

    Not in our library10.1001/jamaneurol.2016.2245

  80. 80.

    Stoker T.B., Camacho M., Winder-Rhodes S., Liu G., Scherzer C.R., Foltynie T., Evans J., Breen D.P., Barker R.A., Williams-Gray C.H. Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry. 2020;91:695-702.

    Not in our library10.1136/jnnp-2020-322857

  81. 81.

    Greuel A., Trezzi J.-P., Glaab E., Ruppert M.C., Maier F., Jäger C., Hodak Z., Lohmann K., Ma Y., Eidelberg D., et al. GBA Variants in Parkinson’s Disease: Clinical, Metabolomic, and Multimodal Neuroimaging Phenotypes. Mov. Disord. 2020;35:2201-2210.

    Not in our library10.1002/mds.28225

  82. 82.

    Mallett V., Ross J.P., Alcalay R.N., Ambalavanan A., Sidransky E., Dion P.A., Rouleau G.A., Gan-Or Z. GBA p.T369M substitution in Parkinson disease: Polymorphism or association? A meta-analysis. Neurology. Genet. 2016;2:e104.

    Not in our library10.1212/nxg.0000000000000104

  83. 83.

    Rosenbloom B., Balwani M., Bronstein J.M., Kolodny E., Sathe S., Gwosdow A.R., Taylor J.S., Cole J.A., Zimran A., Weinreb N.J. The incidence of Parkinsonism in patients with type 1 Gaucher disease: Data from the ICGG Gaucher Registry. Blood Cells Mol. Dis. 2011;46:95-102.

    Not in our library10.1016/j.bcmd.2010.10.006

  84. 84.

    Aharon-Peretz J., Rosenbaum H., Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N. Engl. J. Med. 2004;351:1972-1977.

    Not in our library10.1056/nejmoa033277

  85. 85.

    Chetrit E.B., Alcalay R.N., Steiner-Birmanns B., Altarescu G., Phillips M., Elstein D., Zimran A. Phenotype in patients with Gaucher disease and Parkinson disease. Blood Cells Mol. Dis. 2013;50:218-221.

    Not in our library10.1016/j.bcmd.2012.11.011

  86. 86.
    ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons · 2016
    No notice
  87. 87.

    Alfonso P., Rodriguez-Rey J.C., Ganan A., Perez-Calvo J.I., Giralt M., Giraldo P., Pocovi M. Expression and functional characterization of mutated glucocerebrosidase alleles causing Gaucher disease in Spanish patients. Blood Cells Mol. Dis. 2004;32:218-225.

    Not in our library10.1016/j.bcmd.2003.10.010

  88. 88.

    Grace M.E., Newman K.M., Scheinker V., Bergfussman A., Grabowski G.A. Analysis of Human Acid Beta-Glucosidase by Site-Directed Mutagenesis and Heterologous Expression. J. Biol. Chem. 1994;269:2283-2291.

    Not in our library10.1016/s0021-9258(17)42166-1

  89. 89.

    Ohashi T., Hong C.M., Weiler S., Tomich J.M., Aerts J.M., Tager J.M., Barranger J.A. Characterization of human glucocerebrosidase from different mutant alleles. J. Biol. Chem. 1991;266:3661-3667.

    Not in our library10.1016/s0021-9258(19)67845-2

  90. 90.
    Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models · 2016
    No notice
  91. 91.

    Maor G., Rencus-Lazar S., Filocamo M., Steller H., Segal D., Horowitz M. Unfolded protein response in Gaucher disease: From human to Drosophila. Orphanet J. Rare Dis. 2013;8:140.

    Not in our library10.1186/1750-1172-8-140

  92. 92.

    Schöndorf D.C., Aureli M., McAllister F.E., Hindley C.J., Mayer F., Schmid B., Sardi S.P., Valsecchi M., Hoffmann S., Schwarz L.K., et al. iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun. 2014;5:4028.

    Not in our library10.1038/ncomms5028

  93. 93.

    Ron I., Horowitz M. ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum. Mol. Genet. 2005;14:2387-2398.

    Not in our library10.1093/hmg/ddi240

  94. 94.

    Bendikov-Bar I., Ron I., Filocamo M., Horowitz M. Characterization of the ERAD process of the L444P mutant glucocerebrosidase variant. Blood Cells Mol. Dis. 2011;46:4-10.

    Not in our library10.1016/j.bcmd.2010.10.012

  95. 95.

    Migdalska-Richards A., Wegrzynowicz M., Rusconi R., Deangeli G., Di Monte D.A., Spillantini M.G., Schapira A.H.V. The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice. Brain A J. Neurol. 2017;140:2706-2721.

    Not in our library10.1093/brain/awx221

  96. 96.

    Yun S.P., Kim D., Kim S., Kim S., Karuppagounder S.S., Kwon S.-H., Lee S., Kam T.-I., Lee S., Ham S., et al. α-Synuclein accumulation and GBA deficiency due to L444P GBA mutation contributes to MPTP-induced parkinsonism. Mol. Neurodegener. 2018;13:1.

    Not in our library10.1186/s13024-017-0233-5

  97. 97.

    Huang Y., Deng L., Zhong Y., Yi M. The Association between E326K of GBA and the Risk of Parkinson’s Disease. Parkinson’s Dis. 2018;2018:1048084.

    Not in our library10.1155/2018/1048084

  98. 98.

    Horowitz M., Pasmanik-Chor M., Ron I., Kolodny E.H. The enigma of the E326K mutation in acid beta-glucocerebrosidase. Mol. Genet. Metab. 2011;104:35-38.

    Not in our library10.1016/j.ymgme.2011.07.002

  99. 99.

    Montfort M., Chabás A., Vilageliu L., Grinberg D. Functional analysis of 13 GBA mutant alleles identified in Gaucher disease patients: Pathogenic changes and “modifier” polymorphisms. Hum. Mutat. 2004;23:567-575.

    Not in our library10.1002/humu.20043

  100. 100.

    Alcalay R.N., Levy O.A., Waters C.C., Fahn S., Ford B., Kuo S.H., Mazzoni P., Pauciulo M.W., Nichols W.C., Gan-Or Z., et al. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain A J. Neurol. 2015;138:2648-2658.

    Not in our library10.1093/brain/awv179

  101. 101.

    Grace M.E., Ashton-Prolla P., Pastores G.M., Soni A., Desnick R.J. Non-pseudogene-derived complex acid beta-glucosidase mutations causing mild type 1 and severe type 2 gaucher disease. J. Clin. Investig. 1999;103:817-823.

    Not in our library10.1172/jci5168

  102. 102.

    Malini E., Grossi S., Deganuto M., Rosano C., Parini R., Dominisini S., Cariati R., Zampieri S., Bembi B., Filocamo M., et al. Functional analysis of 11 novel GBA alleles. Eur. J. Hum. Genet. EJHG. 2014;22:511-516.

    Not in our library10.1038/ejhg.2013.182

  103. 103.

    Alcalay R.N., Wolf P., Chiang M.S.R., Helesicova K., Zhang X.K., Merchant K., Hutten S.J., Scherzer C., Caspell-Garcia C., Blauwendraat C., et al. Longitudinal Measurements of Glucocerebrosidase activity in Parkinson’s patients. Ann. Clin. Transl. Neurol. 2020;7:1816-1830.

    Not in our library10.1002/acn3.51164

  104. 104.

    Torralba M.A., Pérez-Calvo J.I., Pastores G.M., Cenarro A., Giraldo P., Pocoví M. Identification and Characterization of a Novel Mutation c.1090G>T (G325W) and Nine Common Mutant Alleles Leading to Gaucher Disease in Spanish Patients. Blood Cells Mol. Dis. 2001;27:489-495.

    Not in our library10.1006/bcmd.2001.0410

  105. 105.

    Liou B., Kazimierczuk A., Zhang M., Scott C.R., Hegde R.S., Grabowski G.A. Analyses of variant acid beta-glucosidases: Effects of Gaucher disease mutations. J. Biol. Chem. 2006;281:4242-4253.

    Not in our library10.1074/jbc.m511110200

  106. 106.
    Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains · 2012
    No notice
  107. 107.

    Gundner A.L., Duran-Pacheco G., Zimmermann S., Ruf I., Moors T., Baumann K., Jagasia R., van de Berg W.D.J., Kremer T. Path mediation analysis reveals GBA impacts Lewy body disease status by increasing alpha-synuclein levels. Neurobiol. Dis. 2019;121:205-213.

    Not in our library10.1016/j.nbd.2018.09.015

  108. 108.

    Murphy K.E., Gysbers A.M., Abbott S.K., Tayebi N., Kim W.S., Sidransky E., Cooper A., Garner B., Halliday G.M. Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease. Brain A J. Neurol. 2014;137:834-848.

    Not in our library10.1093/brain/awt367

  109. 109.

    Cullen V., Sardi P., Ng J., Xu Y.H., Sun Y., Tomlinson J.J., Kolodziej P., Kahn I., Saftig P., Woulfe J., et al. Acid beta-Glucosidase Mutants Linked to Gaucher Disease, Parkinson Disease, and Lewy Body Dementia Alter alpha-Synuclein Processing. Ann. Neurol. 2011;69:940-953.

    Not in our library10.1002/ana.22400

  110. 110.

    Fishbein I., Kuo Y.M., Giasson B.I., Nussbaum R.L. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation. Brain A J. Neurol. 2014;137:3235-3247.

    Not in our library10.1093/brain/awu291

  111. 111.

    Sardi S.P., Clarke J., Kinnecom C., Tamsett T.J., Li L., Stanek L.M., Passini M.A., Grabowski G.A., Schlossmacher M.G., Sidman R.L., et al. CNS expression of glucocerebrosidase corrects alpha-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc. Natl. Acad. Sci. USA. 2011;108:12101-12106.

    Not in our library10.1073/pnas.1108197108

  112. 112.

    Xu Y.H., Xu K., Sun Y., Liou B., Quinn B., Li R.H., Xue L., Zhang W., Setchell K.D., Witte D., et al. Multiple pathogenic proteins implicated in neuronopathic Gaucher disease mice. Hum. Mol. Genet. 2014;23:3943-3957.

    Not in our library10.1093/hmg/ddu105

  113. 113.

    Xu Y.H., Sun Y., Ran H., Quinn B., Witte D., Grabowski G.A. Accumulation and distribution of alpha-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol. Genet. Metab. 2011;102:436-447.

    Not in our library10.1016/j.ymgme.2010.12.014

  114. 114.

    Ginns E.I., Mak S.K., Ko N., Karlgren J., Akbarian S., Chou V.P., Guo Y., Lim A., Samuelsson S., LaMarca M.L., et al. Neuroinflammation and alpha-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction. Mol. Genet. Metab. 2014;111:152-162.

    Not in our library10.1016/j.ymgme.2013.12.003

  115. 115.

    Manning-Boğ A.B., Schüle B., Langston J.W. Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism. NeuroToxicology. 2009;30:1127-1132.

    Not in our library10.1016/j.neuro.2009.06.009

  116. 116.
    Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage · 2013
    No notice
  117. 117.
    Silencing of Glucocerebrosidase Gene in Drosophila Enhances the Aggregation of Parkinson's Disease Associated α-Synuclein Mutant A53T and Affects Locomotor Activity · 2018
    Not checked
  118. 118.

    Bae E.-J., Yang N.Y., Lee C., Lee H.-J., Kim S., Sardi S.P., Lee S.-J. Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and α-synuclein aggregation. Exp. Mol. Med. 2015;47:e153.

    Not in our library10.1038/emm.2014.128

  119. 119.

    Jo J., Yang L., Tran H.D., Yu W., Sun A.X., Chang Y.Y., Jung B.C., Lee S.J., Saw T.Y., Xiao B., et al. Lewy Body-like Inclusions in Human Midbrain Organoids Carrying Glucocerebrosidase and alpha-Synuclein Mutations. Ann. Neurol. 2021;90:490-505.

    Not in our library10.1002/ana.26166

  120. 120.

    Sardi P.S., Shihabuddin L.S., Sidman R.L., Cheng S.H. Augmenting CNS Glucocerebrosidase Activity as a Therapeutic Strategy for Parkinsonism and Other Gaucher-Related Synucleinopathies. Mol. Ther. 2013;21:S14-S15.

    Not in our library10.1073/pnas.1220464110

  121. 121.

    Woodard C.M., Campos B.A., Kuo S.H., Nirenberg M.J., Nestor M.W., Zimmer M., Mosharov E.V., Sulzer D., Zhou H.Y., Paull D., et al. iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease. Cell Rep. 2014;9:1173-1182.

    Not in our library10.1016/j.celrep.2014.10.023

  122. 122.

    Yang J., Hertz E., Zhang X., Leinartaite L., Lundius E.G., Li J., Svenningsson P. Overexpression of alpha-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity. Neurosci. Lett. 2016;611:51-58.

    Not in our library10.1016/j.neulet.2015.11.023

  123. 123.

    Mazzulli J.R., Xu Y.H., Sun Y., Knight A.L., McLean P.J., Caldwell G.A., Sidransky E., Grabowski G.A., Krainc D. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146:37-52.

    Not in our library10.1016/j.cell.2011.06.001

  124. 124.

    Henderson M.X., Sedor S., McGeary I., Cornblath E.J., Peng C., Riddle D.M., Li H.L., Zhang B., Brown H.J., Olufemi M.F., et al. Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological alpha-Synuclein Insult. Neuron. 2020;105:822-836.e7.

    Not in our library10.1016/j.neuron.2019.12.004

  125. 125.

    Dermentzaki G., Dimitriou E., Xilouri M., Michelakakis H., Stefanis L. Loss of β-Glucocerebrosidase Activity Does Not Affect Alpha-Synuclein Levels or Lysosomal Function in Neuronal Cells. PLoS ONE. 2013;8:e60674.

    Not in our library10.1371/journal.pone.0060674

  126. 126.
    Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease · 2019
    Corrected
  127. 127.

    Rocha E.M., Smith G.A., Park E., Cao H., Brown E., Hallett P., Isacson O. Progressive decline of glucocerebrosidase in aging and Parkinson’s disease. Ann. Clin. Transl. Neurol. 2015;2:433-438.

    Not in our library10.1002/acn3.177

  128. 128.
    Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies · 2018
    No notice
  129. 129.
    Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies · 2015
    No notice
  130. 130.

    Parnetti L., Chiasserini D., Persichetti E., Eusebi P., Varghese S., Qureshi M.M., Dardis A., Deganuto M., De Carlo C., Castrioto A., et al. Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson’s disease. Mov. Disord. Off. J. Mov. Disord. Soc. 2014;29:1019-1027.

    Not in our library10.1002/mds.25772

  131. 131.

    Atashrazm F., Hammond D., Perera G., Dobson-Stone C., Mueller N., Pickford R., Kim W.S., Kwok J.B., Lewis S.J.G., Halliday G.M., et al. Reduced glucocerebrosidase activity in monocytes from patients with Parkinson’s disease. Sci. Rep. 2018;8:15446.

    Not in our library10.1038/s41598-018-33921-x

  132. 132.

    Wang F., Song W., Brancati G., Segatori L. Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases. J. Biol. Chem. 2011;286:43454-43464.

    Not in our library10.1074/jbc.m111.274332

  133. 133.

    Braunstein H., Maor G., Chicco G., Filocamo M., Zimran A., Horowitz M. UPR activation and CHOP mediated induction of GBA1 transcription in Gaucher disease. Blood Cells Mol. Dis. 2018;68:21-29.

    Not in our library10.1016/j.bcmd.2016.10.025

  134. 134.

    Kurzawa-Akanbi M., Hanson P.S., Blain P.G., Lett D.J., McKeith I.G., Chinnery P.F., Morris C.M. Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease. J. Neurochem. 2012;123:298-309.

    Not in our library10.1111/j.1471-4159.2012.07879.x

  135. 135.

    Korkotian E., Schwarz A., Pelled D., Schwarzmann G., Segal M., Futerman A.H. Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J. Biol. Chem. 1999;274:21673-21678.

    Not in our library10.1074/jbc.274.31.21673

  136. 136.

    Stojkovska I., Wani W.Y., Zunke F., Belur N.R., Pavlenko E.A., Mwenda N., Sharma K., Francelle L., Mazzulli J.R. Rescue of α-synuclein aggregation in Parkinson’s patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron. 2022;110:436-451.e411.

    Not in our library10.1016/j.neuron.2021.10.032

  137. 137.

    Klionsky D.J., Emr S.D. Autophagy as a regulated pathway of cellular degradation. Science. 2000;290:1717-1721.

    Not in our library10.1126/science.290.5497.1717

  138. 138.

    Yang S.Y., Beavan M., Chau K.Y., Taanman J.W., Schapira A.H. A Human Neural Crest Stem Cell-Derived Dopaminergic Neuronal Model Recapitulates Biochemical Abnormalities in GBA1 Mutation Carriers. Stem Cell Rep. 2017;8:728-742.

    Not in our library10.1016/j.stemcr.2017.01.011

  139. 139.

    Rocha E.M., Smith G.A., Park E., Cao H., Graham A.-R., Brown E., McLean J.R., Hayes M.A., Beagan J., Izen S.C., et al. Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice. Antioxid. Redox Signal. 2015;23:550-564.

    Not in our library10.1089/ars.2015.6307

  140. 140.
    Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease—Links to Parkinson’s Disease · 2013
    No notice
  141. 141.

    Du T.T., Wang L., Duan C.L., Lu L.L., Zhang J.L., Gao G., Qiu X.B., Wang X.M., Yang H. GBA deficiency promotes SNCA/alpha-synuclein accumulation through autophagic inhibition by inactivated PPP2A. Autophagy. 2015;11:1803-1820.

    Not in our library10.1080/15548627.2015.1086055

  142. 142.
    Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease · 2016
    No notice
  143. 143.
    Glucocerebrosidase activity, cathepsin D and monomeric α-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation · 2020
    Not checked
  144. 144.

    Klucken J., Poehler A.-M., Ebrahimi-Fakhari D., Schneider J., Nuber S., Rockenstein E., Schlötzer-Schrehardt U., Hyman B.T., McLean P.J., Masliah E., et al. Alpha-synuclein aggregation involves a bafilomycin A(1)-sensitive autophagy pathway. Autophagy. 2012;8:754-766.

    Not in our library10.4161/auto.19371

  145. 145.

    Kuo S.H., Tasset I., Cheng M.M., Diaz A., Pan M.K., Lieberman O.J., Hutten S.J., Alcalay R.N., Kim S., Ximénez-Embún P., et al. Mutant glucocerebrosidase impairs α-synuclein degradation by blockade of chaperone-mediated autophagy. Sci. Adv. 2022;8:eabm6393.

    Not in our library10.1126/sciadv.abm6393

  146. 146.

    Emmanouilidou E., Melachroinou K., Roumeliotis T., Garbis S.D., Ntzouni M., Margaritis L.H., Stefanis L., Vekrellis K. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 2010;30:6838-6851.

    Not in our library10.1523/jneurosci.5699-09.2010

  147. 147.

    Bae E.J., Yang N.Y., Song M., Lee C.S., Lee J.S., Jung B.C., Lee H.J., Kim S., Masliah E., Sardi S.P., et al. Glucocerebrosidase depletion enhances cell-to-cell transmission of alpha-synuclein. Nat. Commun. 2014;5:4755.

    Not in our library10.1038/ncomms5755

  148. 148.

    Gegg M.E., Verona G., Schapira A.H.V. Glucocerebrosidase deficiency promotes release of alpha-synuclein fibrils from cultured neurons. Hum. Mol. Genet. 2020;29:1716-1728.

    Not in our library10.1093/hmg/ddaa085

  149. 149.
    Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission · 2011
    No notice
  150. 150.

    Cerri S., Ghezzi C., Ongari G., Croce S., Avenali M., Zangaglia R., Di Monte D.A., Valente E.M., Blandini F. GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson’s Disease. Int. J. Mol. Sci. 2021;22:2215.

    Not in our library10.3390/ijms22042215

  151. 151.
    Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles. · 2021
    Not checked
  152. 152.

    Thomas R.E., Vincow E.S., Merrihew G.E., MacCoss M.J., Davis M.Y., Pallanck L.J. Glucocerebrosidase deficiency promotes protein aggregation through dysregulation of extracellular vesicles. PLoS Genet. 2018;14:e1007694.

    Not in our library10.1371/journal.pgen.1007694

  153. 153.

    Migdalska-Richards A., Wegrzynowicz M., Harrison I.F., Verona G., Bellotti V., Spillantini M.G., Schapira A.H.V. L444P Gba1 mutation increases formation and spread of α-synuclein deposits in mice injected with mouse α-synuclein pre-formed fibrils. PLoS ONE. 2020;15:e0238075.

    Not in our library10.1371/journal.pone.0238075

  154. 154.
    Lipid Droplets in Neurodegenerative Disorders · 2020
    No notice
  155. 155.

    Barber M., Baldwin A., Gilbert R., Muller H. Glucocerebrosidase rescues alpha-synuclein from amyloid formation. bioRxiv. 2018.

    Not in our library10.1101/363986

  156. 156.

    Galvagnion C., Brown J.W.P., Ouberai M.M., Flagmeier P., Vendruscolo M., Buell A.K., Sparr E., Dobson C.M. Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of α-synuclein. Proc. Natl. Acad. Sci. USA. 2016;113:7065-7070.

    Not in our library10.1073/pnas.1601899113

  157. 157.

    Farfel-Becker T., Vitner E.B., Kelly S.L., Bame J.R., Duan J., Shinder V., Merrill A.H., Dobrenis K., Futerman A.H. Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Hum. Mol. Genet. 2014;23:843-854.

    Not in our library10.1093/hmg/ddt468

  158. 158.

    Melo F., Caballero L., Zamorano E., Ventura N., Navarro C., Doll I., Zamorano P., Cornejo A. The Cytotoxic Effect of alpha-Synuclein Aggregates. Chemphyschem. 2021;22:526-532.

    Not in our library10.1002/cphc.202000831

  159. 159.

    Fabelo N., Martin V., Santpere G., Marin R., Torrent L., Ferrer I., Diaz M. Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol. Med. 2011;17:1107-1118.

    Not in our library10.2119/molmed.2011.00119

  160. 160.

    Sardi S.P., Viel C., Clarke J., Treleaven C.M., Richards A.M., Park H., Olszewski M.A., Dodge J.C., Marshall J., Makino E., et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc. Natl. Acad. Sci. USA. 2017;114:2699-2704.

    Not in our library10.1073/pnas.1616152114

  161. 161.

    Nagata M., Izumi Y., Ishikawa E., Kiyotake R., Doi R., Iwai S., Omahdi Z., Yamaji T., Miyamoto T., Bamba T., et al. Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity. Proc. Natl. Acad. Sci. USA. 2017;114:E3285-E3294.

    Not in our library10.1073/pnas.1618133114

  162. 162.

    Orvisky E., Park J.K., LaMarca M.E., Ginns E.I., Martin B.M., Tayebi N., Sidransky E. Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: Correlation with phenotype and genotype. Mol. Genet. Metab. 2002;76:262-270.

    Not in our library10.1016/s1096-7192(02)00117-8

  163. 163.

    Hallett P.J., Huebecker M., Brekk O.R., Moloney E.B., Rocha E.M., Priestman D.A., Platt F.M., Isacson O. Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain. Neurobiol. Aging. 2018;67:189-200.

    Not in our library10.1016/j.neurobiolaging.2018.02.028

  164. 164.

    Galvagnion C., Cerri S., Schapira A.H.V., Blandini F., Di Monte D.A. Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation. bioRxiv. 2020.

    Not in our library10.1093/brain/awab371

  165. 165.
    Lipid composition of microdomains is altered in a cell model of Gaucher disease* · 2008
    Not checked
  166. 166.

    Varela A.R., Ventura A.E., Carreira A.C., Fedorov A., Futerman A.H., Prieto M., Silva L.C. Pathological levels of glucosylceramide change the biophysical properties of artificial and cell membranes. Phys. Chem. Chem. Phys. 2016;19:340-346.

    Not in our library10.1039/c6cp07227e

  167. 167.
    No evidence for substrate accumulation in Parkinson brains with GBA mutations · 2015
    No notice
  168. 168.
    Gene-wise association of variants in four lysosomal storage disorder genes in neuropathologically confirmed Lewy body disease. · 2015
    Not checked
  169. 169.

    Nilsson O., Svennerholm L. Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J. Neurochem. 1982;39:709-718.

    Not in our library10.1111/j.1471-4159.1982.tb07950.x

  170. 170.

    Taguchi Y.V., Liu J., Ruan J., Pacheco J., Zhang X., Abbasi J., Keutzer J., Mistry P.K., Chandra S.S. Glucosylsphingosine Promotes alpha-Synuclein Pathology in Mutant GBA-Associated Parkinson’s Disease. J. Neurosci. 2017;37:9617-9631.

    Not in our library10.1523/jneurosci.1525-17.2017

  171. 171.

    Paul A., Jacoby G., Laor Bar-Yosef D., Beck R., Gazit E., Segal D. Glucosylceramide Associated with Gaucher Disease Forms Amyloid-like Twisted Ribbon Fibrils That Induce alpha-Synuclein Aggregation. ACS Nano. 2021;15:11854-11868.

    Not in our library10.1021/acsnano.1c02957

  172. 172.

    Zunke F., Moise A.C., Belur N.R., Gelyana E., Stojkovska I., Dzaferbegovic H., Toker N.J., Jeon S., Fredriksen K., Mazzulli J.R. Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2018;97:92-107.e10.

    Not in our library10.1016/j.neuron.2017.12.012

  173. 173.

    Glajch K.E., Moors T.E., Chen Y., Bechade P.A., Nam A.Y., Rajsombath M.M., McCaffery T.D., Dettmer U., Weihofen A., Hirst W.D., et al. Wild-type GBA1 increases the alpha-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice. Proc. Natl. Acad. Sci. USA. 2021;118:e2103425118.

    Not in our library10.1073/pnas.2103425118

  174. 174.

    Guedes L.C., Chan R.B., Gomes M.A., Conceicao V.A., Machado R.B., Soares T., Xu Y., Gaspar P., Carrico J.A., Alcalay R.N., et al. Serum lipid alterations in GBA-associated Parkinson’s disease. Parkinsonism Relat. Disord. 2017;44:58-65.

    Not in our library10.1016/j.parkreldis.2017.08.026

  175. 175.

    Moloney E.B., Moskites A., Ferrari E.J., Isacson O., Hallett P.J. The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson’s disease patients and increases after lysosomal stress. Neurobiol. Dis. 2018;120:1-11.

    Not in our library10.1016/j.nbd.2018.08.013

  176. 176.

    Murugesan V., Liu J., Yang R., Lin H., Lischuk A., Pastores G., Zhang X., Chuang W.L., Mistry P.K. Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease. Blood Cells Mol. Dis. 2018;68:47-53.

    Not in our library10.1016/j.bcmd.2016.12.002

  177. 177.

    Schapira A.H., Gegg M. Mitochondrial contribution to Parkinson’s disease pathogenesis. Parkinsons Dis. 2011;2011:159160.

    Not in our library10.4061/2011/159160

  178. 178.

    Schapira A.H., Cooper J.M., Dexter D., Clark J.B., Jenner P., Marsden C.D. Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 1990;54:823-827.

    Not in our library10.1111/j.1471-4159.1990.tb02325.x

  179. 179.

    Schapira A.H., Cooper J.M., Dexter D., Jenner P., Clark J.B., Marsden C.D. Mitochondrial complex I deficiency in Parkinson’s disease. Lancet. 1989;1:1269.

    Not in our library10.1016/s0140-6736(89)92366-0

  180. 180.

    Schapira A.H. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7:97-109.

    Not in our library10.1016/s1474-4422(07)70327-7

  181. 181.

    Kinghorn K.J., Grönke S., Castillo-Quan J.I., Woodling N.S., Li L., Sirka E., Gegg M., Mills K., Hardy J., Bjedov I., et al. A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin. J. Neurosci. 2016;36:11654-11670.

    Not in our library10.1523/jneurosci.4527-15.2016

  182. 182.

    Schöndorf D.C., Ivanyuk D., Baden P., Sanchez-Martinez A., De Cicco S., Yu C., Giunta I., Schwarz L.K., Di Napoli G., Panagiotakopoulou V., et al. The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease. Cell Rep. 2018;23:2976-2988.

    Not in our library10.1016/j.celrep.2018.05.009

  183. 183.

    Tansey M.G., Goldberg M.S. Neuroinflammation in Parkinson’s disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 2010;37:510-518.

    Not in our library10.1016/j.nbd.2009.11.004

  184. 184.

    Allen M.J., Myer B.J., Khokher A.M., Rushton N., Cox T.M. Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: Increased release of interleukin-6 and interleukin-10. QJM Mon. J. Assoc. Physicians. 1997;90:19-25.

    Not in our library10.1093/qjmed/90.1.19

  185. 185.

    Mistry P.K., Liu J., Yang M., Nottoli T., McGrath J., Jain D., Zhang K., Keutzer J., Chuang W.L., Mehal W.Z., et al. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc. Natl. Acad. Sci. USA. 2010;107:19473-19478.

    Not in our library10.1073/pnas.1003308107

  186. 186.

    Vitner E.B., Salomon R., Farfel-Becker T., Meshcheriakova A., Ali M., Klein A.D., Platt F.M., Cox T.M., Futerman A.H. RIPK3 as a potential therapeutic target for Gaucher’s disease. Nat. Med. 2014;20:204-208.

    Not in our library10.1038/nm.3449

  187. 187.

    Keatinge M., Bui H., Menke A., Chen Y.C., Sokol A.M., Bai Q., Ellett F., Da Costa M., Burke D., Gegg M., et al. Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death. Hum. Mol. Genet. 2015;24:6640-6652.

    Not in our library10.1093/hmg/ddv369

  188. 188.

    Vitner E.B., Farfel-Becker T., Eilam R., Biton I., Futerman A.H. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain A J. Neurol. 2012;135:1724-1735.

    Not in our library10.1093/brain/aws095

  189. 189.

    Enquist I.B., Lo Bianco C., Ooka A., Nilsson E., Mansson J.E., Ehinger M., Richter J., Brady R.O., Kirik D., Karlsson S. Murine models of acute neuronopathic Gaucher disease. Proc. Natl. Acad. Sci. USA. 2007;104:17483-17488.

    Not in our library10.1073/pnas.0708086104

  190. 190.

    Alvarez-Erviti L., Couch Y., Richardson J., Cooper J.M., Wood M.J. Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci. Res. 2011;69:337-342.

    Not in our library10.1016/j.neures.2010.12.020

  191. 191.

    Zhang W., Wang T., Pei Z., Miller D.S., Wu X., Block M.L., Wilson B., Zhang W., Zhou Y., Hong J.S., et al. Aggregated alpha-synuclein activates microglia: A process leading to disease progression in Parkinson’s disease. FASEB J. 2005;19:533-542.

    Not in our library10.1096/fj.04-2751com

  192. 192.

    Lee E.J., Woo M.S., Moon P.G., Baek M.C., Choi I.Y., Kim W.K., Junn E., Kim H.S. Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J. Immunol. 2010;185:615-623.

    Not in our library10.4049/jimmunol.0903480

  193. 193.

    Kim C., Ho D.H., Suk J.E., You S., Michael S., Kang J., Joong Lee S., Masliah E., Hwang D., Lee H.J., et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 2013;4:1562.

    Not in our library10.1038/ncomms2534

  194. 194.

    Thome A.D., Harms A.S., Volpicelli-Daley L.A., Standaert D.G. microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. J. Neurosci. 2016;36:2383-2390.

    Not in our library10.1523/jneurosci.3900-15.2016

  195. 195.
    In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains · 2017
    Not checked
  196. 196.

    Loria F., Vargas J.Y., Bousset L., Syan S., Salles A., Melki R., Zurzolo C. Alpha-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol. 2017;134:789-808.

    Not in our library10.1007/s00401-017-1746-2

  197. 197.

    Ziegler S.G., Eblan M.J., Gutti U., Hruska K.S., Stubblefield B.K., Goker-Alpan O., LaMarca M.E., Sidransky E. Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol. Genet. Metab. 2007;91:195-200.

    Not in our library10.1016/j.ymgme.2007.03.004

  198. 198.

    Angeli A., Mencacci N.E., Duran R., Aviles-Olmos I., Kefalopoulou Z., Candelario J., Rusbridge S., Foley J., Pradhan P., Jahanshahi M., et al. Genotype and phenotype in Parkinson’s disease: Lessons in heterogeneity from deep brain stimulation. Mov. Disord. 2013;28:1370-1375.

    Not in our library10.1002/mds.25535

  199. 199.

    Shemesh E., Deroma L., Bembi B., Deegan P., Hollak C., Weinreb N.J., Cox T.M. Enzyme replacement and substrate reduction therapy for Gaucher disease. Cochrane Database Syst. Rev. 2015;2015:CD010324.

    Not in our library10.1002/14651858.cd010324.pub2

  200. 200.

    Chauhan A., Tikoo A., Kapur A.K., Singh M. The taming of the cell penetrating domain of the HIV Tat: Myths and realities. J. Control. Release Off. J. Control. Release Soc. 2007;117:148-162.

    Not in our library10.1016/j.jconrel.2006.10.031

  201. 201.

    Gillmeister M.P., Betenbaugh M.J., Fishman P.S. Cellular trafficking and photochemical internalization of cell penetrating peptide linked cargo proteins: A dual fluorescent labeling study. Bioconjug. Chem. 2011;22:556-566.

    Not in our library10.1021/bc900445g

  202. 202.

    Fu A., Wang Y., Zhan L., Zhou R. Targeted delivery of proteins into the central nervous system mediated by rabies virus glycoprotein-derived peptide. Pharm. Res. 2012;29:1562-1569.

    Not in our library10.1007/s11095-012-0667-y

  203. 203.

    Fu A., Zhang M., Gao F., Xu X., Chen Z. A novel peptide delivers plasmids across blood-brain barrier into neuronal cells as a single-component transfer vector. PLoS ONE. 2013;8:e59642.

    Not in our library10.1371/journal.pone.0059642

  204. 204.

    Gramlich P.A., Westbroek W., Feldman R.A., Awad O., Mello N., Remington M.P., Sun Y., Zhang W., Sidransky E., Betenbaugh M.J., et al. A peptide-linked recombinant glucocerebrosidase for targeted neuronal delivery: Design, production, and assessment. J. Biotechnol. 2016;221:1-12.

    Not in our library10.1016/j.jbiotec.2016.01.015

  205. 205.

    Ysselstein D., Young T.J., Nguyen M., Padmanabhan S., Hirst W.D., Dzamko N., Krainc D. Evaluation of Strategies for Measuring Lysosomal Glucocerebrosidase Activity. Mov. Disord. 2021;36:2719-2730.

    Not in our library10.1002/mds.28815

  206. 206.

    Kim S., Yun S.P., Lee S., Umanah G.E., Bandaru V.V.R., Yin X., Rhee P., Karuppagounder S.S., Kwon S.-H., Lee H., et al. GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. Proc. Natl. Acad. Sci. USA. 2018;115:798-803.

    Not in our library10.1073/pnas.1700465115

  207. 207.

    Peterschmitt M.J., Saiki H., Hatano T., Gasser T., Isaacson S.H., Gaemers S.J.M., Minini P., Saubadu S., Sharma J., Walbillic S., et al. Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson’s Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial. J. Parkinson’s Dis. 2022;12:557-570.

    Not in our library10.3233/jpd-212714

  208. 208.

    Hudry E., Vandenberghe L.H. Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality. Neuron. 2019;101:839-862.

    Not in our library10.1016/j.neuron.2019.02.017

  209. 209.

    Rocha E.M., Smith G.A., Park E., Cao H., Brown E., Hayes M.A., Beagan J., McLean J.R., Izen S.C., Perez-Torres E., et al. Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons. Neurobiol. Dis. 2015;82:495-503.

    Not in our library10.1016/j.nbd.2015.09.009

  210. 210.

    Sucunza D., Rico A.J., Roda E., Collantes M., González-Aseguinolaza G., Rodríguez-Pérez A.I., Peñuelas I., Vázquez A., Labandeira-García J.L., Broccoli V., et al. Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques. Int. J. Mol. Sci. 2021;22:4825.

    Not in our library10.3390/ijms22094825

  211. 211.
    Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations · 2020
    No notice
  212. 212.

    Zimran A., Altarescu G., Elstein D. Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol. Dis. 2013;50:134-137.

    Not in our library10.1016/j.bcmd.2012.09.006

  213. 213.
    Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells · 2014
    No notice
  214. 214.

    Magalhaes J., Gegg M.E., Migdalska-Richards A., Schapira A.H. Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons. Sci. Rep. 2018;8:1385.

    Not in our library10.1038/s41598-018-19479-8

  215. 215.

    Migdalska-Richards A., Ko W.K., Li Q., Bezard E., Schapira A.H. Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse. 2017;71:e21967.

    Not in our library10.1002/syn.21967

  216. 216.
    Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice · 2016
    No notice
  217. 217.

    Maor G., Cabasso O., Krivoruk O., Rodriguez J., Steller H., Segal D., Horowitz M. The contribution of mutant GBA to the development of Parkinson disease in Drosophila. Hum. Mol. Genet. 2016;25:2712-2727.

    Not in our library10.1093/hmg/ddw129

  218. 218.

    Aflaki E., Borger D.K., Moaven N., Stubblefield B.K., Rogers S.A., Patnaik S., Schoenen F.J., Westbroek W., Zheng W., Sullivan P., et al. A New Glucocerebrosidase Chaperone Reduces α-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism. J. Neurosci. 2016;36:7441-7452.

    Not in our library10.1523/jneurosci.0636-16.2016

  219. 219.

    Bendikov-Bar I., Maor G., Filocamo M., Horowitz M. Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase. Blood Cells Mol. Dis. 2013;50:141-145.

    Not in our library10.1016/j.bcmd.2012.10.007

  220. 220.

    Mazzulli J.R., Zunke F., Tsunemi T., Toker N.J., Jeon S., Burbulla L.F., Patnaik S., Sidransky E., Marugan J.J., Sue C.M., et al. Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson’s Patient Midbrain Neurons. J. Neurosci. 2016;36:7693-7706.

    Not in our library10.1523/jneurosci.0628-16.2016

  221. 221.

    Shanmuganathan M., Britz-McKibbin P. Inhibitor screening of pharmacological chaperones for lysosomal beta-glucocerebrosidase by capillary electrophoresis. Anal. Bioanal. Chem. 2011;399:2843-2853.

    Not in our library10.1007/s00216-011-4671-6

  222. 222.

    Patnaik S., Zheng W., Choi J.H., Motabar O., Southall N., Westbroek W., Lea W.A., Velayati A., Goldin E., Sidransky E., et al. Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. J. Med. Chem. 2012;55:5734-5748.

    Not in our library10.1021/jm300063b

  223. 223.

    Suzuki T., Shimoda M., Ito K., Hanai S., Aizawa H., Kato T., Kawasaki K., Yamaguchi T., Ryoo H.D., Goto-Inoue N., et al. Expression of Human Gaucher Disease Gene GBA Generates Neurodevelopmental Defects and ER Stress in Drosophila Eye. PLoS ONE. 2013;8:e69147.

    Not in our library10.1371/journal.pone.0135619

  224. 224.

    Richter F., Fleming S.M., Watson M., Lemesre V., Pellegrino L., Ranes B., Zhu C., Mortazavi F., Mulligan C.K., Sioshansi P.C., et al. A GCase chaperone improves motor function in a mouse model of synucleinopathy. Neurotherapeutics. 2014;11:840-856.

    Not in our library10.1007/s13311-014-0294-x

  225. 225.

    Morabito G., Giannelli S.G., Ordazzo G., Bido S., Castoldi V., Indrigo M., Cabassi T., Cattaneo S., Luoni M., Cancellieri C., et al. AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy. Mol. Ther. 2017;25:2727-2742.

    Not in our library10.1016/j.ymthe.2017.08.004

  226. 226.

    den Heijer J.M., Kruithof A.C., van Amerongen G., de Kam M.L., Thijssen E., Grievink H.W., Moerland M., Walker M., Been K., Skerlj R., et al. A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator. Br. J. Clin. Pharmacol. 2021;87:3561-3573.

    Not in our library10.1111/bcp.14772

  227. 227.

    Lu J., Yang C., Chen M., Ye D.Y., Lonser R.R., Brady R.O., Zhuang Z. Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease. Proc. Natl. Acad. Sci. USA. 2011;108:21200-21205.

    Not in our library10.1073/pnas.1119181109

  228. 228.

    Yang C., Rahimpour S., Lu J., Pacak K., Ikejiri B., Brady R.O., Zhuang Z. Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones. Proc. Natl. Acad. Sci. USA. 2013;110:966-971.

    Not in our library10.1073/pnas.1221046110

  229. 229.

    Jung O., Patnaik S., Marugan J., Sidransky E., Westbroek W. Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease. Expert Rev. Proteom. 2016;13:471-479.

    Not in our library10.1080/14789450.2016.1174583

  230. 230.

    Bendikov-Bar I., Maor G., Horowitz M. Processing and maturation of human glucocerebrosidase. Advances in Gaucher Disease: Basic and Clinical Perspectives. 2013;140-157.

    Not in our library10.2217/ebo.12.298

  231. 231.

    Khanna R., Benjamin E.R., Pellegrino L., Schilling A., Rigat B.A., Soska R., Nafar H., Ranes B.E., Feng J., Lun Y., et al. The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of beta-glucosidase. FEBS J. 2010;277:1618-1638.

    Not in our library10.1111/j.1742-4658.2010.07588.x

  232. 232.
    Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease · 2010
    Corrected
  233. 233.

    Decressac M., Björklund A. mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats. J. Parkinson’s Dis. 2013;3:13-17.

    Not in our library10.3233/jpd-120155

  234. 234.

    Fog C.K., Zago P., Malini E., Solanko L.M., Peruzzo P., Bornaes C., Magnoni R., Mehmedbasic A., Petersen N.H.T., Bembi B., et al. The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase. EBioMedicine. 2018;38:142-153.

    Not in our library10.1016/j.ebiom.2018.11.037

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