No retraction, correction or concern found when last checked on Oct 22, 2026.

GAP-43 and BASP1 in Axon Regeneration: Implications for the Treatment of Neurodegenerative Diseases

Daayun Chung, Andrew Shum, Gabriela Caraveo

Frontiers in Cell and Developmental Biology · 2020 · Review · CC BY

doi:10.3389/fcell.2020.567537

Abstract

Growth-associated protein-43 (GAP-43) and brain acid-soluble protein 1 (BASP1) regulate actin dynamics and presynaptic vesicle cycling at axon terminals, thereby facilitating axonal growth, regeneration, and plasticity. These functions highly depend on changes in GAP-43 and BASP1 expression levels and post-translational modifications such as phosphorylation. Interestingly, examinations of GAP-43 and BASP1 in neurodegenerative diseases reveal alterations in their expression and phosphorylation profiles. This review provides an overview of the structural properties, regulations, and functions of GAP-43 and BASP1, highlighting their involvement in neural injury response and regeneration. By discussing GAP-43 and BASP1 in the context of neurodegenerative diseases, we also explore the therapeutic potential of modulating their activities to compensate for neuron loss in neurodegenerative diseases.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Axons integrate external cues to grow toward and arborize their terminals onto their correct targets. Such axonal behavior is critical for establishing proper connections, regenerating injured nerves, and retaining anatomical plasticity in adult brains. A group of growth-associated proteins (>100), whose expression is upregulated during neuronal development and regeneration, mediates these functions. Growth-associated protein-43 (GAP-43) and brain acid-soluble protein 1 (BASP1) are two members of this group with many shared structural properties and functions. GAP-43 is solely expressed in the nervous system, whereas BASP1 is highly expressed in the nervous system and some non-neural tissues including the kidney and testis. Within neurons, GAP-43, and BASP1 are enriched in axon terminals, where they regulate the actin cytoskeleton. By modulating actin dynamics, GAP-43, and BASP1 achieve their physiological functions in neurodevelopment, synaptic function, and nerve regeneration.

Neurodevelopment

2Growth-associated protein-43 and BASP1 are highly expressed during periods of active axon growth and synaptogenesis. Their critical involvement in neurodevelopment has been demonstrated by gene knockout studies. Homozygous knockout of GAP-43 (GAP-43–/–) or BASP1 (BASP1–/–) leads to high neonatal lethality, resulting in 5–10% survival to adulthood. Surviving GAP-43–/– animals exhibit defective pathfinding of retinal and commissural axons, as well as an abnormal somatotopic map in the barrel cortex. In reflection of these anatomical defects, GAP-43–/– animals demonstrate motor, sensory, and behavioral impairments. Surviving BASP1–/– animals also present evidence of impaired neurodevelopment including enlarged ventricles in the brain, axonal and synaptic abnormalities in the neocortex and hippocampus, and hyperactive behavior.

Synaptic Function

3As axons complete the innervation of their target areas, GAP-43 and BASP1 are downregulated in most brain regions. Interestingly, they remain highly expressed in areas of the adult brain implicated in learning and memory, including the neocortex and hippocampus. In support of their importance in information storage, heterozygous GAP-43 knockout mice (GAP-43+/–) exhibit a selective impairment in contextual memory. This phenotype can be explained by various synaptic functions of GAP-43. GAP-43 was shown to regulate endocytosis via its interaction with rabaptin-5, which functions in endocytic membrane fusion, and as a substrate of caspase-3, which mediates AMPA receptor endocytosis. Also, antibodies against GAP-43 decreased the release of glutamate and noradrenaline, indicating its importance in neurotransmitter release. This function is thought to be mediated, at least in part, by its interaction with the presynaptic vesicle fusion complex (Syntaxin, SNAP-25, and VAMP). Moreover, GAP-43 was shown to enhance long-term potentiation. The presence of BASP1 on synaptic vesicles and its identification as a caspase-3 substrate suggest its potential role in synaptic vesicle cycling, which may have implications for neurotransmission, synaptic plasticity, and information storage.

Nerve Regeneration

4Another circumstance under which GAP-43 and BASP1 are upregulated is nerve regeneration following injury. An increase in GAP-43 and BASP1 mRNA levels strongly correlates with enhanced regenerative capacity. This is evidenced by their robust upregulation in the regenerating dorsal root ganglion (DRG) axons following sciatic nerve injury but not in the non-regenerating DRG axons following dorsal rhizotomy. The upregulation of GAP-43 and BASP1 also correlated with axonal sprouting after stroke in the barrel cortex. Additionally, an increase in GAP-43 was associated with optogenetic-induced functional recovery from stroke in the primary motor cortex. In a different rodent model of stroke, antisense oligonucleotides to GAP-43 abolished the enhancement of functional recovery induced by the basic fibroblast growth factor. These observations from rodent stroke models hint at the importance of GAP-43 in neuronal recovery following injury. More importantly, GAP-43 was shown to be essential for the regenerative response through knockdown studies. In adult rodents, climbing fibers retain high levels of GAP-43 and demonstrate structural plasticity after injury. Knockdown of GAP-43 in climbing fibers inhibited the sprouting of their axonal branches following laser-axotomy and lesion of the inferior olive, where these fibers originate. Overexpression studies involving GAP-43 and BASP1 show these proteins are sufficient for f-actin accumulation and subsequent neurite formation in primary sensory neurons and in Purkinje neurons. Moreover, co-overexpression of GAP-43 and BASP1 was sufficient to drive the regeneration of DRG axons following spinal cord lesion in adult mice when peripheral nerve graft was provided.

Involvement in Neural Injury Response

5In the central (CNS) and peripheral nervous systems (PNS), different external and internal factors lead to disparate outcomes of injury response. In the CNS, glial scar and inhibitory glial factors such as myelin-associated glycoproteins and Nogo impede neuronal regeneration. Additionally, the inherent lack of axonal integrins and growth factor receptors limit the regrowth of neurons in the CNS. As a result, positive outcomes of CNS injury remain limited to neuroprotection and marginal regenerative response. Neural injury stimulates neurons and glia to release cytokines and neurotrophic factors, which can activate growth-associated proteins such as GAP-43 and BASP1 to promote neuroprotection and regeneration.

Cytokine Signaling

6Upon injury, leakage from damaged or dying cells leads to an excess of glutamate in the extracellular space. This stimulates astrocytes, microglia, and neurons to secrete cytokines such as interleukin-6 (IL-6) and -10 (IL-10). Accordingly, IL-6 and -10 were found to be elevated in the cerebrospinal fluid and serum of patients with severe traumatic brain injury (TBI). After spinal cord injury, IL-6 treatment was shown to activate the JAK/STAT3 and PI3K/Akt pathways, upregulate GAP-43 and BASP1, and promote neurite outgrowth in vitro and synaptogenesis in vivo (,; Figure 1). The upregulation of GAP-43 and BASP1 was sensitive to the JAK2 inhibitor AG490 but was not examined with a PI3K inhibitor. After oxygen-glucose deprivation, IL-10 treatment was shown to activate the JAK/STAT3 and PI3K/Akt pathways, upregulate GAP-43, and facilitate neuroprotection, neurite outgrowth, and synaptogenesis in vitro (;; Figure 1). The upregulation of GAP-43 was shown to be sensitive to the PI3K inhibitor LY294002 but was not examined with a JAK2 inhibitor. The extent to which the neurite outgrowth observed in vitro translates into in vivo regeneration remains unclear.

Neurotrophic Factor Signaling

7Following injury, neurotrophic factors such as the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are upregulated in response to glutamate and cytokines. NGF and BDNF bind tropomyosin receptor kinase A and B, respectively, to initiate cell survival signaling via the PI3K/Akt pathway (; Figure 1). In rodent models of stroke and TBI, the activation of NGF and BDNF signaling was shown to promote neuroprotection, synaptogenesis, and neurogenesis. Such beneficial upregulation of NGF and BDNF was accompanied by an increase in GAP-43 levels when optogenetic stimulations were provided after stroke. Given that BASP1 is similarly upregulated after stroke, its increase may also be mediated by NGF and BDNF. Moreover, GAP-43 was shown to be an essential effector of BDNF-driven neuroprotection.

Intrinsic Disorder and Phase Separation

8Growth-associated protein-43 and BASP1 are acidic proteins with isoelectric points of 4.4–4.6. Their molecular weights are 23–25 kDa, but they appear at higher molecular weights on SDS-PAGE. These proteins are enriched in alanine (22% in GAP-43, 21% in BASP1) and proline (8% in GAP-43, 12% in BASP1), which gives rise to a high content of type II polyproline helix (32 ± 5% in GAP-43, 37 ± 2% in BASP1) characteristic of intrinsically disordered proteins. Nuclear magnetic resonance spectroscopy also indicates that GAP-43 and BASP1 have unordered structures. Intrinsically disordered proteins lack a stable three-dimensional structure and have the ability to engage in multivalent interactions. Through multivalent interactions, intrinsically disordered proteins undergo liquid-liquid phase separation and form membraneless compartments that facilitate their functions. Many proteins involved in actin assembly have intrinsically disordered regions, and phase separation mediated by these regions underlies their regulation of actin dynamics. Moreover, phosphorylation of intrinsically disordered proteins affects phase separation by modulating their charge and electrostatic interactions. Given that GAP-43 and BASP1 are phosphoproteins, they may transmit signals from kinases and phosphatases to the actin cytoskeleton via phase separation.

PEST Sequence and High Turnover Rate

9Growth-associated protein-43 and BASP1 have peptide sequences rich in proline, glutamate, serine, and threonine (PEST). While PEST regions vary in their sequences and lengths, they all serve as signals for rapid proteolysis. The presence of PEST sequences indicates that GAP-43 and BASP1 are short-lived proteins, however, this has yet to be experimentally verified.

Effector Domain and CaM Binding

10Growth-associated protein-43 and BASP1 have regions termed the effector domain (ED) that are enriched in basic and hydrophobic residues, bind calmodulin (CaM), and are phosphorylated by protein kinase C (PKC). The basic and hydrophobic residues in the ED also contribute to membrane association of these proteins. GAP-43 ED consists of residues 37–52 (KIQASFRGHITRKKLK) (; Figure 2), which includes a canonical CaM-binding site termed the IQ motif (IQxxxRGxxxR). GAP-43 was shown to bind CaM with higher affinity in the absence of or at low Ca2+ and to dissociate at high Ca2+. Hence, GAP-43 has been proposed to accumulate CaM at specific sites and release them upon local Ca2+ elevation to sharpen the downstream response. Unlike GAP-43, BASP1 ED is located at the N-terminal end (Myristoylation-GGKLSKKKKGY) (; Figure 2). BASP1 lacks an IQ motif and instead binds CaM through alternating basic and hydrophobic residues. These alternating parts include the myristoyl moiety, which passes through a tunnel formed by hydrophobic pockets in the N- and C-terminal domains of CaM. BASP1 was shown to bind CaM with stronger affinity than GAP-43 and in the presence of Ca2+, suggesting a different mode of action than GAP-43.

Formation of Oligomers

11Growth-associated protein-43 and BASP1 form oligomers in the presence of anionic phospholipids or sodium dodecyl sulfate (SDS). Among anionic phospholipids, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) was the most potent driver of oligomerization. Interestingly, GAP-43 and BASP1 accumulate PI(4,5)P2 on the inner surface of the plasma membrane, and this clustering is important for initiating signaling cascades that regulate the actin cytoskeleton. The role of PI(4,5)P2 in driving oligomerization suggests that PI(4,5)P2-induced oligomers may be important for this process. Oligomerization of GAP-43 and BASP1 results in α-helix formation within their EDs while preserving the overall structural disorder. A significant level of disorder in oligomers has been proposed to enhance the flexibility of interactions and to enable the reversion to monomers. In support of the flexibility in binding, GAP-43 and BASP1 were observed to form heterooligomers of different stoichiometries in vitro and in presynaptic membranes. In agreement with the reversibility, GAP-43 and BASP1 oligomers were shown to dissociate into monomers upon removal of SDS or binding of CaM.

Transcriptional and Post-Transcriptional Regulation

12In developing and regenerating neurons, the levels of GAP-43 and BASP1 mRNAs and proteins are upregulated. Studies present conflicting findings regarding the contributions of transcriptional activation to increased GAP-43 levels. The GAP-43 gene has two promoters, distal (P1) and proximal (P2), that are highly conserved between the rat and human genes. P1 contains classical promoter elements including TATA and CCAAT boxes, as well as a repressive element shown to inhibit GAP-43 expression in non-neuronal cells. P2 lacks classical promoter elements but contains a conserved enhancer box (E1) that can bind basic helix-loop-helix transcription factors, which have critical roles in neural cell fate specification and differentiation. In zebrafish, a 1 kb fragment spanning P1 and P2 of the rat GAP-43 gene was shown to developmentally regulate the expression of a downstream transgene in neurons. In contrast to this finding, developing rat cortical neurons and nerve growth factor-induced PC12 cells showed no change in GAP-43 pre-mRNA levels despite an increase in GAP-43 mRNA levels. This finding indicates that mRNA stability mainly contributes to the observed upregulation of GAP-43. The stabilization of GAP-43 mRNA is dependent on the highly conserved 3′ untranslated region, where the neural-specific RNA-binding protein HuD binds. The expression of HuD and GAP-43 are concomitantly increased during neuritogenesis, in regenerating nerves, and following spatial learning in rodent hippocampi. Based on these observations, HuD was hypothesized to stabilize GAP-43 mRNA under physiological conditions. In support of this hypothesis, transgenic mice overexpressing HuD exhibited an increase in GAP-43 mRNA but not pre-mRNA. Also, the half-life of GAP-43 mRNA from these transgenic mice was significantly longer than those from non-transgenic controls. The HuD-dependent stabilization of GAP-43 mRNA is positively regulated by PKC and is inhibited by the KH-type splicing regulatory protein, which competes with HuD to bind and promote the degradation of GAP-43 mRNA. Compared to GAP-43, little is known about the transcriptional and post-transcriptional control of BASP1. In the chicken BASP1 gene, a 135 bp region in the 5′ end of exon 1 was shown to bind the transcription factors Sp1 and Myc. This regulatory region was sufficient to activate transcription and to mediate Myc-induced suppression of BASP1. Additionally, post-transcriptional regulation of BASP1 by its processed pseudogene has been proposed but not experimentally verified.

Fatty Acylation

13Growth-associated protein-43 and BASP1 mainly localize to membranes, and their membrane associations are partially mediated by fatty acylation. GAP-43 is post-translationally palmitoylated at Cysteine-3 and -4 (; Figure 2). Its palmitoylation can occur in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), Golgi apparatus, and plasma membrane. Upon palmitoylation, GAP-43 can be sorted to the tips of growing neurites. Palmitoylation of GAP-43 is dynamically regulated, as suggested by the low percentage (∼35%) of fatty acylated GAP-43 at steady state in PC12 and COS-1 cells. The dynamic regulation of palmitoylation affects GAP-43 functions. Changes in palmitoylation enable GAP-43 to cycle between pathways independent of and involving Go, a heterotrimeric GTP-binding protein enriched in growth cones. N-terminal peptides of GAP-43 produced by the Ca2+-dependent protease m-calpain interact with and activate Go signaling cascade that leads to growth cone collapse (;; Figure 3). Palmitoylation reduces the ability of the N-terminal peptides to stimulate Go, thereby blocking Go signaling-induced growth cone collapse. Additionally, palmitoylation appears to be important for the switch from promoting axon growth to stabilizing synapses upon successful target innervation. Experimental evidence shows that palmitoylation of GAP-43, when inhibited, reversibly stalls neurite outgrowth and is significantly reduced at the early phase of synapse maturation. Unlike GAP-43, BASP1 is co-translationally myristoylated at the N-terminal end (;; Figure 2). In the rat brain, BASP1 molecules and N-terminal fragments appear predominantly in the myristoylated form. Myristoylation of BASP1 was shown to promote membrane association and to enable CaM binding.

Phosphorylation

14Growth-associated protein-43 and BASP1 EDs undergo Ca2+-dependent phosphorylation by PKC. PKC phosphosites in GAP-43 and BASP1 are Serine-41 and Serine-6, respectively (;; Figure 2). GAP-43 Serine-41 can also be dephosphorylated by the Ca2+/CaM-dependent phosphatase calcineurin (CaN). Phosphorylation by PKC abolishes CaM binding to both GAP-43 and BASP1. More importantly, PKC-mediated phosphorylation has significant functional consequences. Phosphorylated GAP-43 not only promotes actin polymerization and stabilization but also interacts with presynaptic vesicle fusion complex (Syntaxin, SNAP-25, and VAMP). Through these molecular pathways, phosphorylated GAP-43 facilitates axon guidance, axon outgrowth, neurotransmission, and synaptic plasticity. The modulation of BASP1 functions by PKC remains to be studied. In addition to PKC phosphosites, many residues of GAP-43 and BASP1 were found to be phosphorylated. To name a few, GAP-43 was phosphorylated at Serine-96 and Threonine-172 by unknown kinase(s), Serine-191 and -192 by Casein Kinase II, and Serine-96 by c-Jun N-terminal kinase (JNK) (; Figure 2). Additional phosphosites on GAP-43 (Serine-86, Threonine-95, and Threonine-172) and BASP1 (Threonine-31, Serine-40, Serine-170) were found to be sensitive to CaN (; Figure 2). The phosphorylation of GAP-43 and BASP1 at these other residues may be of functional significance. For example, JNK phosphorylates GAP-43 in growth cone membranes, and this modification is associated with axon growth and regeneration.

Mechanisms of Actin Cytoskeleton Regulation

15Regulation of the actin cytoskeleton is important for axon guidance and growth, endocytosis, and exocytosis. Therefore, understanding how GAP-43 and BASP1 modulate actin dynamics provides insight into the mechanisms through which they achieve their physiological functions. To test if GAP-43 and BASP1 perform their functions through identical pathways, knockin mice expressing GAP-43 in place of BASP1 was generated. While these mice exhibited no gross abnormality in the brain, they showed small morphological differences in axon sprouts. This indicates that GAP-43 and BASP1 act through partially redundant pathways, a concept that was reinforced by observations of phenotypic differences between GAP-43- and BASP1-induced neurite outgrowth and of synergistic axon sprouting with co-overexpression of GAP-43 and BASP1.

Signaling Through PI(4,5)P2 Clusters

16Growth-associated protein-43 and BASP1 regulate actin dynamics through a shared pathway involving PI(4,5)P2. In the intracellular surface of cholesterol-rich rafts, GAP-43 and BASP1 co-distribute with and promote the clustering of PI(4,5)P2. Concentrating PI(4,5)P2 in local environments is thought to enhance the recruitment of actin-regulating proteins. These proteins include WASP and ERM proteins known for their roles in actin polymerization and actin cytoskeleton-membrane crosslinking, respectively. The functions of WASP and ERM proteins contribute to growth cone motility and outgrowth (Figure 3).

PKC-Dependent Modulation of Actin

17Growth-associated protein-43 binds and directly regulates actin filaments in a PKC-dependent manner. Phosphorylated GAP-43 binds actin with higher affinity (Kd = 161 nM) compared to the unphosphorylated form (Kd = 1.2 uM). In accordance with this enhanced binding, the cytoskeletal association of GAP-43 increases with phosphorylation. Moreover, phosphorylated GAP-43 stabilizes actin filaments, thereby promoting growth cone extension and motility (; Figure 3). On the other hand, unphosphorylated GAP-43 inhibits growth cone extension likely by serving as a barbed end-capping protein. Capping proteins significantly increase the concentration of actin monomers needed for polymerization and attenuate actin assembly, which is critical for growth cone extension. While BASP1 may similarly regulate the actin cytoskeleton, this hypothesis remains to be tested.

Functional Association With NCAM-180 and Spectrin

18Growth-associated protein-43 has also been proposed to modulate actin dynamics through the functional association with the neural cell adhesion molecule-180 (NCAM-180) and the cytoskeletal protein spectrin (; Figure 3). NCAMs engage in homophilic and heterophilic binding with components of other cells and the extracellular matrix (ECM). These interactions, in addition to establishing cell-cell and cell-ECM adhesions, initiate intracellular signaling cascades important for neuronal development, synaptic plasticity, and regeneration. NCAMs directly associate with intracellular signaling molecules to activate these downstream cascades. NCAM-180 has been shown to mediate neurite outgrowth by interacting with spectrin, and spectrin was shown to bind GAP-43. Based on these observations, NCAM-180, spectrin, and GAP-43 have been hypothesized to function in a complex to mediate neurite outgrowth. In support of this hypothesis, NCAM-mediated neurite outgrowth, in the presence of GAP-43, required functional NCAM-180 and spectrin. BASP1 was shown to function independently of this mechanism in PC12 cells and hippocampal neurons, where BASP1 failed to substitute the stimulation of NCAM-mediated neurite outgrowth by GAP-43.

Intrinsic Disorder and Phase Separation in Pathological Protein Aggregation

19Growth-associated protein-43 and BASP1 are intrinsically disordered proteins. The functional significance of this property remains understudied in both physiological and pathological contexts. In many neurodegenerative diseases, intrinsically disordered proteins form soluble and fibril aggregates that are central to the pathogenesis. The recent discovery of liquid-liquid phase separation, which condensates disordered proteins, gained interest as a potential mechanism of pathological protein aggregation. Furthermore, proteins forming aggregates in neurodegenerative diseases such as Tau and Huntingtin were shown to undergo phase separation. The involvement of disordered proteins in neurodegenerative diseases questions whether GAP-43 and BASP1 also phase separate in this context, whether this process turns aberrant, and what the functional consequences are.

Post-transcriptional Regulation in Neurodegenerative Diseases

20Post-transcriptional regulation allows a rapid adjustment of the location and level of protein expression. This spatiotemporal regulation is particularly important in neurons because of their large and complex morphology. A key regulator of this process is the neuron-specific RNA-binding protein HuD. HuD post-transcriptionally regulates GAP-43 during neuritogenesis, regeneration, and learning. Interestingly, HuD is associated with various neurodegenerative disorders. The level of HuD was shown to be decreased in the hippocampus of Alzheimer’s Disease patients. This decrease correlated with diminished expression of ADAM10, a protein known to reduce the generation of pathogenic amyloid-β peptides. From genetic studies, HuD was also identified as a susceptibility gene for Parkinson’s Disease. Additionally, HuD was shown to aberrantly interact with FUS mutant that is causally linked to Amyotrophic Lateral Sclerosis. In light of these findings, the post-transcriptional regulation of GAP-43 may be dysregulated in neurodegenerative disorders.

PKC and CaM in Neurodegenerative Diseases

21Growth-associated protein-43 and BASP1 engage in intracellular Ca2+ signaling through PKC and CaM. Ca2+ signaling plays a central role in neuronal physiology, and Ca2+ dyshomeostasis contributes to the pathogenesis of neurodegenerative disorders. As part of Ca2+ signaling cascades, PKC and CaM significantly impact the disease states.

22Protein kinase C has a vital role in memory encoding and storage; therefore, its involvement in Alzheimer’s Disease – a major form of dementia – has been studied extensively. Few studies showed that the activity of PKC is decreased in the brains of Alzheimer’s Disease patients, suggesting potential adverse effects of its diminished activity. In alignment with this finding, the PKC activator bryostatin reduced the production of amyloid-β peptides and premature mortality in mouse models of Alzheimer’s Disease. On the other hand, whole genome-sequencing of late-onset Alzheimer’s Disease patients identified gain-of-function mutations in PKC. This study demonstrated that enhanced PKC activity mediates synaptic depression induced by amyloid-β peptides. Other studies also linked PKC activation to synaptic changes such as reduced cell-surface expression of AMPA receptor and dysregulated structural plasticity. These findings point to the importance of balanced PKC activity in neuronal physiology. They also raise the possibility that PKC-dependent functions of GAP-43 and BASP1 affect cellular pathways whose dyshomeostasis contribute to neurodegenerative diseases.

23Calmodulin connects Ca2+ signals to cellular functions through various effector proteins. These effectors include Ca2+/CaM-dependent kinases and phosphatases like CaMKII and CaN. CaMKII and CaN critically regulate synaptic functions and contribute to synaptopathy in neurodegenerative diseases. CaM also affects pathogenic processes such as Ca2+ dysregulation and pathogenic protein fibrillation by directly binding the plasma membrane Ca2+ APTase (PCMA) and amyloid-β peptides. Likewise, CaM binding by GAP-43 and BASP1 may directly and indirectly affect processes involved in neurodegenerative disorders.

Functions of GAP-43 and BASP1 and Their Link to Neurodegenerative Diseases

24Growth-associated protein-43 and BASP1 regulate the actin cytoskeleton, which in turn modulates axon outgrowth and synaptic functions. Actin dynamics are altered in neurodegenerative disorders, and this change culminates in structural defects and synaptic dysfunctions. Disruption of dendritic actin filaments were observed in Drosophila models of polyglutamine diseases. This disruption was associated with decreased dendritic complexity – an early deficit that may contribute to the pathogenesis. Similarly, decreased levels of synaptosomal actin filaments were detected in mouse models and patient brains of Alzheimer’s Disease. This reduction inversely correlated with dendritic spine density and behavioral performance. Moreover, in Drosophila, pathogenic tau mutant and amyloid-β promoted abnormal accumulation and bundling of actin filaments, which correlated with neurotoxicity.

25In addition, actin binding proteins contribute to the pathogenesis of neurodegenerative disorders. For instance, the actin depolymerizing factor cofilin was found to be hyperactivated in Alzheimer’s Disease. The accumulation of hyperactivated cofilin formed cofilin-actin rods that led to impaired synaptic functions and synapse loss. Conversely, the level of the actin stabilizing protein drebrin was dramatically reduced in Alzheimer’s Disease. A reduction in drebrin levels impaired neuritogenesis, resulted in synaptic dysfunctions, and correlated with cognitive impairment. These findings warrant examination of the actin regulators GAP-43 and BASP1 in neurodegenerative diseases.

Regulation of GAP-43 and BASP1 in Neurodegenerative Diseases

26Growth-associated protein-43 and BASP1 were examined in many neurodegenerative diseases – Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy – through studies of human patients and cellular and animal models. Most of these studies present correlational changes in GAP-43 and BASP1 but do not address their functional implications. In the following sections, GAP-43 and BASP1 will be discussed in the context of Alzheimer’s and Parkinson’s Disease, two neurodegenerative diseases in which they have been studied the most.

Alzheimer’s Disease

27Alzheimer’s Disease (AD) is the most common neurodegenerative disorder causing dementia. AD is neuropathologically characterized by extracellular amyloid beta (Aβ) deposits termed amyloid plaques and intracellular neurofibrillary tangles composed of the microtubule-binding protein tau. While AD involves a widespread loss of neurons, it primarily affects cholinergic neurons in the basal forebrain, noradrenergic neurons in the locus coeruleus, and pyramidal neurons in the entorhinal cortex, subiculum, and hippocampal CA1. These vulnerable neurons have long and thin axons with sparse myelination. Such axonal properties increase the energetic demand and exposure to pathogenic species that contribute to the vulnerability in AD. Immunohistochemical studies found that GAP-43 levels were decreased in the neocortex but was preserved or even elevated in the hippocampus of AD patients. The reduction in cortical GAP-43 immunoreactivity likely reflects a profound neuron loss. The preservation or increase in hippocampal GAP-43 immunoreactivity raises the possibility that surviving neurons, by upregulating GAP-43, initiate axon outgrowth to compensate for the lost connections. Hippocampal GAP-43 immunoreactivity was observed in dystrophic neurites associated with plaques and correlated with aberrant sprouting, which is characteristic of synaptic pathology in AD. Based on this observation, GAP-43-associated axon outgrowth appears to be unsuccessful in establishing functional connections and seems to be contributing to the synaptic pathology instead. Examination of entorhinal fibers in amyloid precursor protein transgenic mice provides evidence that this aberrant sprouting is driven by amyloid deposition. This finding highlights the importance of extrinsic factors on the successful regenerative response and emphasizes the need for combined therapy that overcomes both extrinsic and intrinsic barriers to axon remodeling. In agreement with the immunohistochemical data, quantitative mass spectrometry detected a reduction of GAP-43 in the temporal neocortex of AD patients. The same study also measured decreased levels of BASP1 in AD patients. In addition to their changes in expression, the extent of their phosphorylation was altered in AD. The overall phosphorylation of both proteins decreased in the temporal lobe of AD patients compared to non-AD individuals. For a detailed analysis of the phosphoproteome over the course of disease progression, four mouse models of AD at early, middle, and late time points were examined with respect to control mice. This analysis identified 5 phosphosites in GAP-43 and 6 phosphosites in BASP1 (Figure 2 shows equivalent sites in rat proteins based on sequence alignment in Clustal Omega; ). Phosphorylation at these sites generally increased in the middle stage of pathology and progressively decreased. Although the physiological relevance of these changes remains to be examined, this study prompts us to explore the possibility of modulating GAP-43 and BASP1 phosphorylation for therapeutic interventions in AD.

Parkinson’s Disease

28Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder. PD is neuropathologically characterized by the accumulation of α-synuclein inclusions termed Lewy bodies. In PD, dopaminergic neurons in the substantia nigra pars compacta (SNc) primarily degenerate, causing motor symptoms such as bradykinesia, rigidity, and tremor. The axons of the SNc dopaminergic neurons are long, thin, and poorly myelinated. Additionally, they branch extensively in the striatum and form extraordinarily large numbers of synapses with transmitter release sites numbering up to 300,000. These axonal properties contribute to the selective vulnerability in PD. A transcriptome-based meta-analysis of multiple studies found that GAP-43 and BASP1 are downregulated in the brains of PD patients. This same study identified BASP1 as an important regulator of other differentially expressed genes associated with synaptic signaling. Immunoreactivity of tyrosine hydroxylase (TH), a marker for dopaminergic neurons, was reduced in the SNc and striatum of PD patients in reflection of a substantial neuron loss. However, in the remaining TH+ SNc dopaminergic neurons, GAP-43 protein and mRNA levels were likewise decreased. In agreement with these data, reduced GAP-43 expression has also been detected in the cerebral spinal fluid of PD patients. Further evidence implicates the involvement of GAP-43 and BASP1 in PD. In an in vitro scratch lesion model using α-syn mutations causing autosomal-dominant forms of PD, the study found reduced neurite regeneration and subsequent loss of dopaminergic neurons accompanied by a reduction of striatal expression of GAP-43. In one PD patient, infusion with glial cell-derived neurotrophic factor at the putamen provided benefits even after cessation of treatment. While these reports suggest that increasing GAP-43 expression and therefore the axonal tree would be beneficial, other groups suggest that reduction of the axonal tree, in fact, confers protection in models of PD. The apparent discrepancy between these studies can be addressed if taken into consideration that the effect in neuronal sprouting needs to be regulated. In support of this idea, one study found that modulation of the activity of GAP-43 and BASP1 through CaN can alter the degeneration of axonal trees and confer neuroprotection in a rat model of PD. This model displayed presynaptic and behavioral impairments along with hypophosphorylation at 3 CaN-sensitive sites each in GAP-43 and BASP1 (Figure 2; ). Treatment with low doses of Tacrolimus, which partially inhibits CaN, ameliorated the presynaptic and behavioral deficits in addition to rescuing phosphorylation at these sites. This correlation suggests a potential involvement of GAP-43 and BASP1 phosphorylation in PD pathogenesis. Interestingly, Tacrolimus is an FDA-approved drug currently in widespread clinical use at high doses to suppress the rejection of organs in transplant patients, a process in which CaN also plays a critical role. This opens the possibility that Tacrolimus could be repurposed as a potential therapy for the treatment of PD.

Concluding Remarks

29Growth-associated protein-43 and BASP1 are essential for developing axons to grow toward their correct targets and form synaptic connections during neuronal development and after neural injury. These axonal functions highly depend on their expression levels and phosphorylation status, which when modulated appropriately, can stimulate mature neurons to re- enter a growth state. This transition, which can protect and enable surviving neurons to re-establish functional connections, has been explored as a therapeutic avenue for neurodegenerative diseases. Specifically, the effects of delivering agents that upregulate GAP-43, such as BDNF, have been tested in animal models of PD. BDNF treatment, although unable to revert neurodegeneration, demonstrated protective effects on remaining neurons and ameliorated behavioral impairments. Several investigations into understanding the mechanism of potential therapies have identified GAP-43 as either upregulated or essential for its ameliorative effects. Levetiracetam for treatment of retinopathy as well as for the repair of convulsant- induced cognitive impairment directly signals through the PKC/GAP-43 signaling pathway. Similarly, TGN-020 for treatment of spinal cord injury, and senegenin for the potential treatment for Aβ-induced neurotoxicity, involve upregulation of GAP-43 protein levels for both neuroprotection and in vitro regeneration. Low GAP-43 levels in cerebrospinal fluid were associated with a poorer response to treatment of primary progressive multiple sclerosis using fingolimod or alemtuzumab suggesting that GAP-43 is important in mediating its therapeutic effects. In rat models of PD, treatments with Pilose antler extracts led to an increase in striatal GAP-43 protein expression and less dopaminergic SNc neuronal cell death. Despite the positive effects of neurotrophic factors in animal models, their short half-life, low bioavailability, and limited permeability through the blood-brain barrier (BBB) imposed challenges in their application to patients. Such challenges associated with using neurotrophic factors to increase GAP-43 and BASP1 levels can be avoided by using other pharmacological agents that can cross the BBB and modulate their activities, for instance, via phosphorylation. A potential candidate is the FDA-approved CaN inhibitor Tacrolimus. In a rat model of PD, tacrolimus was shown to cross the BBB, alter phosphorylation of GAP-43 and BASP1, and confer neuroprotection at doses 10-fold lower than the standard immunosuppressive dose. At sub-immunosuppressive doses, the risk of secondary effects, such as opportunistic infections, posterior reversible leukoencephalopathy, and seizures typically achieved at clinical doses would be avoided. Moreover, these lower Tacrolimus doses would finely tune GAP-43 and BASP1 to drive sufficient, but not hyperactive, axonal sprouting in a spatially and temporally confined manner. This regulation is necessary to promote regeneration specifically in the affected neuronal populations at the right time window while preventing potential complications arising from hyperconnectivity. Additionally, external inhibitory factors in the central nervous system and other disease-associated factors need to be prevented from blocking axon growth or driving the formation of aberrant connections. Moreover, determining the stages of pathogenesis at which regeneration of remaining axons can be protective will be important. Further exploration of these areas will facilitate the development of GAP-43- and BASP1-targeting therapies for neurodegenerative diseases.

Author Contributions

30DC contributed by writing and revising the entire review, as well as generating figures. AS contributed to writing the section “Involvement in Neural Injury Response” and building Figure 1. GC conceived the review, contributed to the concluding remarks, and edited the review. All authors contributed to the article and approved the submitted version.

Conflict of Interest

31The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 224

1.
Acarin L. González B. Castellano B. (2000 ). Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. Eur. J. Neurosci. 12 3505–3520.
Not in our library10.1046/j.1460-9568.2000.00226.x
2.
Aigner L. Arber S. Kapfhammer J. P. Laux T. Schneider C. Botteri F. (1995 ). Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell 83 269–278.
Not in our library10.1016/0092-8674(95)90168-x
3.
Aigner L. Caroni P. (1995 ). Absence of persistent spreading, branching, and adhesion in GAP-43-depleted growth cones. J. Cell Biol. 128 647–660.
Not in our library10.1083/jcb.128.4.647
4.
Alexander K. A. Cimler B. M. Meier K. E. Storm D. R. (1987 ). Regulation of calmodulin binding to P-57. A neurospecific calmodulin binding protein. J. Biol. Chem. 262 6108–6113.
Not in our library
5.
Alfonso S. I. Callender J. A. Hooli B. Antal C. E. Mullin K. Sherman M. A. (2016 ). Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease. Sci. Signal. 9:ra47
Not in our library10.1126/scisignal.aaf6209
6.
Allegra Mascaro A. L. Cesare P. Sacconi L. Grasselli G. Mandolesi G. Maco B. (2013 ). In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex. Proc. Natl. Acad. Sci. U.S.A. 110 10824–10829.
Not in our library10.1073/pnas.1219256110
7.
Amadio M. Pascale A. Wang J. Ho L. Quattrone A. Gandy S. (2009 ). nELAV proteins alteration in Alzheimer’s disease brain: a novel putative target for amyloid-beta reverberating on AbetaPP processing. J. Alzheimers Dis. 16 409–419.
Not in our library10.3233/jad-2009-0967
8.
Anderson K. D. Merhege M. A. Morin M. Bolognani F. Perrone-Bizzozero N. I. (2003 ). Increased expression and localization of the RNA-binding protein HuD and GAP-43 mRNA to cytoplasmic granules in DRG neurons during nerve regeneration. Exp. Neurol. 183 100–108.
Not in our library10.1016/s0014-4886(03)00103-1
9.
Anderson K. D. Sengupta J. Morin M. Neve R. L. Valenzuela C. F. Perrone-Bizzozero N. I. (2001 ). Overexpression of HuD accelerates neurite outgrowth and increases GAP-43 mRNA expression in cortical neurons and retinoic acid-induced embryonic stem cells in vitro. Exp. Neurol. 168 250–258.
Not in our library10.1006/exnr.2000.7599
10.
Andreasen T. J. Luetje C. W. Heideman W. Storm D. R. (1983 ). Purification of a novel calmodulin binding protein from bovine cerebral cortex membranes. Biochemistry 22 4615–4618.
Not in our library10.1021/bi00289a001
11.
Andrés-Benito P. Moreno J. Aso E. Povedano M. Ferrer I. (2017 ). Amyotrophic lateral sclerosis, gene deregulation in the anterior horn of the spinal cord and frontal cortex area 8: implications in frontotemporal lobar degeneration. Aging 9 823–851.
Not in our library10.18632/aging.101195
12.
Apel E. D. Byford M. F. Au D. Walsh K. A. Storm D. R. (1990 ). Identification of the protein kinase C phosphorylation site in neuromodulin. Biochemistry 29 2330–2335.
Not in our library10.1021/bi00461a017
13.
Apel E. D. Litchfield D. W. Clark R. H. Krebs E. G. Storm D. R. (1991 ). Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin. J. Biol. Chem. 266 10544–10551.
Not in our library
14.
Apostol B. L. Illes K. Pallos J. Bodai L. Wu J. Strand A. (2006 ). Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum. Mol. Genet. 15 273–285.
Not in our library10.1093/hmg/ddi443
15.
Aumiller W. M. Keating C. D. (2016 ). Phosphorylation-mediated RNA/peptide complex coacervation as a model for intracellular liquid organelles. Nat. Chem. 8 129–137.
Not in our library10.1038/nchem.2414
16.
Bähler M. Rhoads A. (2002 ). Calmodulin signaling via the IQ motif. FEBS Lett. 513 107–113.
Not in our library10.1016/s0014-5793(01)03239-2
17.
Bamburg J. R. Bernstein B. W. Davis R. C. Flynn K. C. Goldsbury C. Jensen J. R. (2010 ). ADF/Cofilin-actin rods in neurodegenerative diseases. Curr. Alzheimer Res. 7 241–250.
Not in our library10.2174/156720510791050902
18.
Barker W. W. Luis C. A. Kashuba A. Luis M. Harwood D. G. Loewenstein D. (2002 ). Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis. Assoc. Disord. 16 203–212.
Not in our library10.1097/00002093-200210000-00001
19.
Barnes J. A. Gomes A. V. (1995 ). PEST sequences in calmodulin-binding proteins. Mol. Cell. Biochem. 149-150 17–27.
Not in our library10.1007/978-1-4615-2015-3_2
20.
Benowitz L. I. Apostolides P. J. Perrone-Bizzozero N. Finklestein S. P. Zwiers H. (1988 ). Anatomical distribution of the growth-associated protein GAP-43/B-50 in the adult rat brain. J. Neurosci. 8 339–352.
Not in our library10.1523/jneurosci.08-01-00339.1988
21.
Berrocal M. Sepulveda M. R. Vazquez-Hernandez M. Mata A. M. (2012 ). Calmodulin antagonizes amyloid-β peptides-mediated inhibition of brain plasma membrane Ca(2+)-ATPase. Biochim. Biophys. Acta 1822 961–969.
Not in our library10.1016/j.bbadis.2012.02.013
22.
Bezprozvanny I. (2009 ). Calcium signaling and neurodegenerative diseases. Trends Mol. Med. 15 89–100.
Not in our library10.1016/j.molmed.2009.01.001
23.
KSRP modulation of GAP-43 mRNA stability restricts axonal outgrowth in embryonic hippocampal neurons. · 2013
Not checked
24.
Blanquie O. Bradke F. (2018 ). Cytoskeleton dynamics in axon regeneration. Curr. Opin. Neurobiol. 51 60–69.
Not in our library10.1016/j.conb.2018.02.024
25.
Bogdanovic N. Davidsson P. Volkmann I. Winblad B. Blennow K. (2000 ). Growth-associated protein GAP-43 in the frontal cortex and in the hippocampus in Alzheimer’s disease: an immunohistochemical and quantitative study. J. Neural Transm. 107 463–478.
Not in our library10.1007/s007020070088
26.
Living on the edge with too many mouths to feed: Why dopamine neurons die · 2012
No notice
27.
Bolognani F. Tanner D. C. Merhege M. Deschenes-Furry J. Jasmin B. Perrone-Bizzozero N. I. (2006 ). In vivo post-transcriptional regulation of GAP-43 mRNA by overexpression of the RNA-binding protein HuD. J. Neurochem. 96 790–801.
Not in our library10.1111/j.1471-4159.2005.03607.x
28.
Bomze H. M. Bulsara K. R. Iskandar B. J. Caroni P. Skene J. H. (2001 ). Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Nat. Neurosci. 4 38–43.
Not in our library10.1038/82881
29.
Bondareff W. Mountjoy C. Q. Roth M. (1982 ). Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia. Neurology 32 164–168.
Not in our library10.1212/wnl.32.2.164
30.
Braak H. Del Trecidi K. (2015 ). Neuroanatomy and pathology of sporadic Alzheimer’s disease. Adv. Anat. Embryol. Cell Biol. 215 1–162.
Not in our library10.1007/978-3-540-79850-7_1
31.
Braak H. Ghebremedhin E. Rüb U. Bratzke H. Del Tredici K. (2004 ). Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 318 121–134.
Not in our library10.1007/s00441-004-0956-9
32.
Bronicki L. M. Jasmin B. J. (2013 ). Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction. RNA 19 1019–1037.
Not in our library10.1261/rna.039164.113
33.
Buffo A. Holtmaat A. J. Savio T. Verbeek J. S. Oberdick J. Oestreicher A. B. (1997 ). Targeted overexpression of the neurite growth-associated protein B-50/GAP-43 in cerebellar Purkinje cells induces sprouting after axotomy but not axon regeneration into growth-permissive transplants. J. Neurosci. 17 8778–8791.
Not in our library10.1523/jneurosci.17-22-08778.1997
34.
Bullock R. Zauner A. Woodward J. J. Myseros J. Choi S. C. Ward J. D. (1998 ). Factors affecting excitatory amino acid release following severe human head injury. J. Neurosurg. 89 507–518.
Not in our library10.3171/jns.1998.89.4.0507
35.
Calabrese B. Halpain S. (2005 ). Essential role for the PKC target MARCKS in maintaining dendritic spine morphology. Neuron 48 77–90.
Not in our library10.1016/j.neuron.2005.08.027
36.
Caraveo G. Soste M. Cappelleti V. Fanning S. Van Rossum D. B. Whitesell L. (2017 ). FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome. Proc. Natl. Acad. Sci. U.S.A. 114 E11313–E11322.
Not in our library10.1073/pnas.1711926115
37.
Carmichael S. T. Archibeque I. Luke L. Nolan T. Momiy J. Li S. (2005 ). Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex. Exp. Neurol. 193 291–311.
Not in our library10.1016/j.expneurol.2005.01.004
38.
Caroni P. (2001 ). New EMBO member’s review: actin cytoskeleton regulation through modulation of PI(4,5)P(2) rafts. EMBO J. 20 4332–4336.
Not in our library10.1093/emboj/20.16.4332
39.
Caroni P. Aigner L. Schneider C. (1997 ). Intrinsic neuronal determinants locally regulate extrasynaptic and synaptic growth at the adult neuromuscular junction. J. Cell Biol. 136 679–692.
Not in our library10.1083/jcb.136.3.679
40.
Chen H. Lin W. Zhang Y. Lin L. Chen J. Zeng Y. (2016 ). IL-10 promotes neurite outgrowth and synapse formation in cultured cortical neurons after the oxygen-glucose deprivation via JAK1/STAT3 pathway. Sci. Rep. 6 30459–30416.
Not in our library10.1038/srep30459
41.
Cheng M. Y. Wang E. H. Woodson W. J. Wang S. Sun G. Lee A. G. (2014 ). Optogenetic neuronal stimulation promotes functional recovery after stroke. Proc. Natl. Acad. Sci. U.S.A. 111 12913–12918.
Not in our library10.1073/pnas.1404109111
42.
Chiaramello A. Neuman T. Peavy D. R. Zuber M. X. (1996 ). The GAP-43 gene is a direct downstream target of the basic helix-loop-helix transcription factors. J. Biol. Chem. 271 22035–22043.
Not in our library10.1074/jbc.271.36.22035
43.
Chiaretti A. Barone G. Riccardi R. Antonelli A. Pezzotti P. Genovese O. (2009 ). NGF, DCX, and NSE upregulation correlates with severity and outcome of head trauma in children. Neurology 72 609–616.
Not in our library10.1212/01.wnl.0000342462.51073.06
44.
Chin D. Means A. R. (2000 ). Calmodulin: a prototypical calcium sensor. Trends Cell Biol. 10 322–328.
Not in our library10.1016/s0962-8924(00)01800-6
45.
Chiti F. Dobson C. M. (2006 ). Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75 333–366.
Not in our library10.1146/annurev.biochem.75.101304.123901
46.
Chung S. Eckrich M. Perrone-Bizzozero N. Kohn D. T. Furneaux H. (1997 ). The Elav-like proteins bind to a conserved regulatory element in the 3′-untranslated region of GAP-43 mRNA. J. Biol. Chem. 272 6593–6598.
Not in our library10.1074/jbc.272.10.6593
47.
Cichon J. Sun C. Chen B. Jiang M. Chen X. A. Sun Y. (2012 ). Cofilin aggregation blocks intracellular trafficking and induces synaptic loss in hippocampal neurons. J. Biol. Chem. 287 3919–3929.
Not in our library10.1074/jbc.m111.301911
48.
Cimler B. M. Andreasen T. J. Andreasen K. I. Storm D. R. (1985 ). P-57 is a neural specific calmodulin-binding protein. J. Biol. Chem. 260 10784–10788.
Not in our library
49.
Corbacho I. Berrocal M. Török K. Mata A. M. Gutierrez-Merino C. (2017 ). High affinity binding of amyloid β-peptide to calmodulin: structural and functional implications. Biochem. Biophys. Res. Commun. 486 992–997.
Not in our library10.1016/j.bbrc.2017.03.151
50.
Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. · 2002
Not checked
51.
Counts S. E. Nadeem M. Lad S. P. Wuu J. Mufson E. J. (2006 ). Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J. Neuropathol. Exp. Neurol. 65 592–601.
Not in our library10.1097/00005072-200606000-00007
52.
Csuka E. Morganti-Kossmann M. C. Lenzlinger P. M. Joller H. Trentz O. Kossmann T. (1999 ). IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J. Neuroimmunol. 101 211–221.
Not in our library10.1016/s0165-5728(99)00148-4
53.
de Groen P. C. Eggen B. J. Gispen W. H. Schotman P. Schrama L. H. (1995 ). Cloning and promoter analysis of the human B-50/GAP-43 gene. J. Mol. Neurosci. 6 109–119.
Not in our library10.1007/bf02736770
54.
De La Monte S. M. Federoff H. J. Ng S. C. Grabczyk E. Fishman M. C. (1989 ). GAP-43 gene expression during development: persistence in a distinctive set of neurons in the mature central nervous system. Brain Res. Dev. Brain Res. 46 161–168.
Not in our library10.1016/0165-3806(89)90279-4
55.
De La Monte S. M. Ng S. C. Hsu D. W. (1995 ). Aberrant GAP-43 gene expression in Alzheimer’s disease. Am. J. Pathol. 147 934–946.
Not in our library
56.
De Santis R. Alfano V. De Turris V. Colantoni A. Santini L. Garone M. G. (2019 ). Mutant FUS and ELAVL4 (HuD) aberrant crosstalk in amyotrophic lateral sclerosis. Cell Rep. 27:3818.
Not in our library10.1016/j.celrep.2019.05.085
57.
Dekker L. V. De Graan P. N. Oestreicher A. B. Versteeg D. H. Gispen W. H. (1989a ). Inhibition of noradrenaline release by antibodies to B-50 (GAP-43). Nature 342 74–76.
Not in our library10.1038/342074a0
58.
Dekker L. V. De Graan P. N. Versteeg D. H. Oestreicher A. B. Gispen W. H. (1989b ). Phosphorylation of B-50 (GAP43) is correlated with neurotransmitter release in rat hippocampal slices. J. Neurochem. 52 24–30.
Not in our library10.1111/j.1471-4159.1989.tb10893.x
59.
DeKosky S. T. Goss J. R. Miller P. D. Styren S. D. Kochanek P. M. Marion D. (1994 ). Upregulation of nerve growth factor following cortical trauma. Exp. Neurol. 130 173–177.
Not in our library10.1006/exnr.1994.1196
60.
Dennis D. J. Han S. Schuurmans C. (2019 ). bHLH transcription factors in neural development, disease, and reprogramming. Brain Res. 1705 48–65.
Not in our library10.1016/j.brainres.2018.03.013
61.
Dent E. W. Meiri K. F. (1998 ). Distribution of phosphorylated GAP-43 (neuromodulin) in growth cones directly reflects growth cone behavior. J. Neurobiol. 35 287–299.
Not in our library10.1002/(sici)1097-4695(19980605)35:3<287::aid-neu6>3.0.co;2-v
62.
DeStefano A. L. Latourelle J. Lew M. F. Suchowersky O. Klein C. Golbe L. I. (2008 ). Replication of association between ELAVL4 and Parkinson disease: the GenePD study. Hum. Genet. 124 95–99.
Not in our library10.1007/s00439-008-0526-4
63.
Ditlevsen D. K. Povlsen G. K. Berezin V. Bock E. (2008 ). NCAM-induced intracellular signaling revisited. J. Neurosci. Res. 86 727–743.
Not in our library10.1002/jnr.21551
64.
Dong X. Cong S. (2018 ). Identification of differentially expressed genes and regulatory relationships in Huntington’s disease by bioinformatics analysis. Mol. Med. Rep. 17 4317–4326.
Not in our library10.3892/mmr.2018.8410
65.
Edmonds B. T. Moomaw C. R. Hsu J. T. Slaughter C. Ellis L. (1990 ). The p38 and p34 polypeptides of growth cone particle membranes are the alpha- and beta-subunits of G proteins. Brain Res. Dev. Brain Res. 56 131–136.
Not in our library10.1016/0165-3806(90)90172-u
66.
Eggen B. J. Nielander H. B. Rensen-De Leeuw M. G. Schotman P. Gispen W. H. Schrama L. H. (1994 ). Identification of two promoter regions in the rat B-50/GAP-43 gene. Brain Res. Mol. Brain Res. 23 221–234.
Not in our library10.1016/0169-328x(94)90229-1
67.
Eitzen G. (2003 ). Actin remodeling to facilitate membrane fusion. Biochim. Biophys. Acta 1641 175–181.
Not in our library10.1016/s0167-4889(03)00087-9
68.
Elbaum-Garfinkle S. (2019 ). Matter over mind: liquid phase separation and neurodegeneration. J. Biol. Chem. 294 7160–7168.
Not in our library10.1074/jbc.rev118.001188
69.
Etcheberrigaray R. Tan M. Dewachter I. Kuipéri C. Van Der Auwera I. Wera S. (2004 ). Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 101 11141–11146.
Not in our library10.1073/pnas.0403921101
70.
Fallini C. Donlin-Asp P. G. Rouanet J. P. Bassell G. J. Rossoll W. (2016 ). Deficiency of the survival of motor neuron protein impairs mRNA localization and local translation in the growth cone of motor neurons. J. Neurosci. 36 3811–3820.
Not in our library10.1523/jneurosci.2396-15.2016
71.
Filbin M. T. (2003 ). Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat. Rev. Neurosci. 4 703–713.
Not in our library10.1038/nrn1195
72.
Forsova O. S. Zakharov V. V. (2016 ). High-order oligomers of intrinsically disordered brain proteins BASP1 and GAP-43 preserve the structural disorder. FEBS J. 283 1550–1569.
Not in our library10.1111/febs.13692
73.
Fournier A. E. Strittmatter S. M. (2001 ). Repulsive factors and axon regeneration in the CNS. Curr. Opin. Neurobiol. 11 89–94.
Not in our library10.1016/s0959-4388(00)00178-1
74.
Frey D. Laux T. Xu L. Schneider C. Caroni P. (2000 ). Shared and unique roles of CAP23 and GAP43 in actin regulation, neurite outgrowth, and anatomical plasticity. J. Cell Biol. 149 1443–1454.
Not in our library10.1083/jcb.149.7.1443
75.
Fulga T. A. Elson-Schwab I. Khurana V. Steinhilb M. L. Spires T. L. Hyman B. T. (2007 ). Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell Biol. 9 139–148.
Not in our library10.1038/ncb1528
76.
Gamby C. Waage M. C. Allen R. G. Baizer L. (1996 ). Analysis of the role of calmodulin binding and sequestration in neuromodulin (GAP-43) function. J. Biol. Chem. 271 26698–26705.
Not in our library10.1074/jbc.271.43.26698
77.
Gauthier-Kemper A. Igaev M. Sündermann F. Janning D. Brühmann J. Moschner K. (2014 ). Interplay between phosphorylation and palmitoylation mediates plasma membrane targeting and sorting of GAP43. Mol. Biol. Cell 25 3284–3299.
Not in our library10.1091/mbc.e13-12-0737
78.
Geist L. Zawadzka-Kazimierczuk A. Saxena S. Żerko S. Koźmiński W. Konrat R. (2013 ). 1H,13C and 15N resonance assignments of human BASP1. Biomol. NMR Assign. 7 315–319.
Not in our library10.1007/s12104-012-9436-4
79.
Geraldo S. Khanzada U. K. Parsons M. Chilton J. K. Gordon-Weeks P. R. (2008 ). Targeting of the F-actin-binding protein drebrin by the microtubule plus-tip protein EB3 is required for neuritogenesis. Nat. Cell Biol. 10 1181–1189.
Not in our library10.1038/ncb1778
80.
Goedert M. Wischik C. M. Crowther R. A. Walker J. E. Klug A. (1988 ). Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. U.S.A. 85 4051–4055.
Not in our library10.1073/pnas.85.11.4051
81.
Gomez T. M. Letourneau P. C. (2014 ). Actin dynamics in growth cone motility and navigation. J. Neurochem. 129 221–234.
Not in our library10.1111/jnc.12506
82.
Grasselli G. Mandolesi G. Strata P. Cesare P. (2011 ). Impaired sprouting and axonal atrophy in cerebellar climbing fibres following in vivo silencing of the growth-associated protein GAP-43. PLoS One 6:e20791.
Not in our library10.1371/journal.pone.0020791
83.
Grasselli G. Strata P. (2013 ). Structural plasticity of climbing fibers and the growth-associated protein GAP-43. Front. Neural Circuits 7:25
Not in our library10.3389/fncir.2013.00025
84.
Gu Z. Liu W. Yan Z. (2009 ). {beta}-Amyloid impairs AMPA receptor trafficking and function by reducing Ca2+/calmodulin-dependent protein kinase II synaptic distribution. J. Biol. Chem. 284 10639–10649.
Not in our library10.1074/jbc.m806508200
85.
Gudasheva T. A. Povarnina P. Y. Volkova A. A. Kruglov S. V. Antipova T. A. Seredenin S. B. (2019 ). A nerve growth factor dipeptide mimetic stimulates neurogenesis and synaptogenesis in the hippocampus and striatum of adult rats with focal cerebral ischemia. Acta Nat. 11 31–37.
Not in our library10.32607/20758251-2019-11-3-31-37
86.
Gupta S. K. Mishra R. Kusum S. Spedding M. Meiri K. F. Gressens P. (2009 ). GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986. Cell Death Differ. 16 624–637.
Not in our library10.1038/cdd.2008.188
87.
Gwag B. J. Sessler F. M. Robine V. Springer J. E. (1997 ). Endogenous glutamate levels regulate nerve growth factor mRNA expression in the rat dentate gyrus. Mol. Cells 7 425–430.
Not in our library
88.
Han M.-H. Jiao S. Jia J.-M. Chen Y. Chen C. Y. Gucek M. (2013 ). The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression. Mol. Cell. Proteomics 12 3719–3731.
Not in our library10.1074/mcp.m113.030676
89.
Harigaya Y. Shoji M. Shirao T. Hirai S. (1996 ). Disappearance of actin-binding protein, drebrin, from hippocampal synapses in Alzheimer’s disease. J. Neurosci. Res. 43 87–92.
Not in our library10.1002/jnr.490430111
90.
Hartl M. Nist A. Khan M. I. Valovka T. Bister K. (2009 ). Inhibition of Myc-induced cell transformation by brain acid-soluble protein 1 (BASP1). Proc. Natl. Acad. Sci. U.S.A. 106 5604–5609.
Not in our library10.1073/pnas.0812101106
91.
Haruta T. Takami N. Ohmura M. Misumi Y. Ikehara Y. (1997 ). Ca2+-dependent interaction of the growth-associated protein GAP-43 with the synaptic core complex. Biochem. J. 325(Pt 2), 455–463.
Not in our library10.1042/bj3250455
92.
Hatanpää K. Isaacs K. R. Shirao T. Brady D. R. Rapoport S. I. (1999 ). Loss of proteins regulating synaptic plasticity in normal aging of the human brain and in Alzheimer disease. J. Neuropathol. Exp. Neurol. 58 637–643.
Not in our library10.1097/00005072-199906000-00008
93.
Intrinsic Disorder Is a Common Feature of Hub Proteins from Four Eukaryotic Interactomes · 2006
No notice
94.
He Q. Dent E. W. Meiri K. F. (1997 ). Modulation of actin filament behavior by GAP-43 (neuromodulin) is dependent on the phosphorylation status of serine 41, the protein kinase C site. J. Neurosci. 17 3515–3524.
Not in our library10.1523/jneurosci.17-10-03515.1997
95.
Heemskerk F. M. Schrama L. H. Gianotti C. Spierenburg H. Versteeg D. H. De Graan P. N. (1990 ). 4-Aminopyridine stimulates B-50 (GAP43) phosphorylation and [3H]noradrenaline release in rat hippocampal slices. J. Neurochem. 54 863–869.
Not in our library10.1111/j.1471-4159.1990.tb02331.x
96.
Hens J. J. Ghijsen W. E. Weller U. Spierenburg H. A. Boomsma F. Oestreicher A. B. (1998 ). Anti-B-50 (GAP-43) antibodies decrease exocytosis of glutamate in permeated synaptosomes. Eur. J. Pharmacol. 363 229–240.
Not in our library10.1016/s0014-2999(98)00835-8
97.
Hess D. T. Patterson S. I. Smith D. S. Skene J. H. (1993 ). Neuronal growth cone collapse and inhibition of protein fatty acylation by nitric oxide. Nature 366 562–565.
Not in our library10.1038/366562a0
98.
Hulo S. Alberi S. Laux T. Muller D. Caroni P. (2002 ). A point mutant of GAP-43 induces enhanced short-term and long-term hippocampal plasticity. Eur. J. Neurosci. 15 1976–1982.
Not in our library10.1046/j.1460-9568.2002.02026.x
99.
Hyman B. T. Van Hoesen G. W. Damasio A. R. Barnes C. L. (1984 ). Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225 1168–1170.
Not in our library10.1126/science.6474172
100.
Ikemoto A. Hirano A. Akiguchi I. (1999 ). Increased expression of growth-associated protein 43 on the surface of the anterior horn cells in amyotrophic lateral sclerosis. Acta Neuropathol. 98 367–373.
Not in our library10.1007/s004010051096
101.
Jacobson R. D. Virág I. Skene J. H. (1986 ). A protein associated with axon growth, GAP-43, is widely distributed and developmentally regulated in rat CNS. J. Neurosci. 6 1843–1855.
Not in our library10.1523/jneurosci.06-06-01843.1986
102.
Jesky R. Chen H. (2016 ). The neuritogenic and neuroprotective potential of senegenin against Aβ-induced neurotoxicity in PC 12 cells. BMC Complement. Altern. Med. 16:26.
Not in our library10.1186/s12906-016-1006-3
103.
Karns L. R. Ng S. C. Freeman J. A. Fishman M. C. (1987 ). Cloning of complementary DNA for GAP-43, a neuronal growth-related protein. Science 236 597–600.
Not in our library10.1126/science.2437653
104.
Kawamata T. Ren J. Cha J. H. Finklestein S. P. (1999 ). Intracisternal antisense oligonucleotide to growth associated protein-43 blocks the recovery-promoting effects of basic fibroblast growth factor after focal stroke. Exp. Neurol. 158 89–96.
Not in our library10.1006/exnr.1999.7101
105.
Growth Cone Phosphoproteomics Reveals that GAP-43 Phosphorylated by JNK Is a Marker of Axon Growth and Regeneration · 2018
Not checked
106.
Kohn D. T. Tsai K. C. Cansino V. V. Neve R. L. Perrone-Bizzozero N. I. (1996 ). Role of highly conserved pyrimidine-rich sequences in the 3′ untranslated region of the GAP-43 mRNA in mRNA stability and RNA-protein interactions. Brain Res. Mol. Brain Res. 36 240–250.
Not in our library10.1016/0169-328x(95)00239-o
107.
Kojima N. Shirao T. (2007 ). Synaptic dysfunction and disruption of postsynaptic drebrin-actin complex: a study of neurological disorders accompanied by cognitive deficits. Neurosci. Res. 58 1–5.
Not in our library10.1016/j.neures.2007.02.003
108.
Aβ mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease · 2017
No notice
109.
Korshunova I. Caroni P. Kolkova K. Berezin V. Bock E. Walmod P. S. (2008 ). Characterization of BASP1-mediated neurite outgrowth. J. Neurosci. Res. 86 2201–2213.
Not in our library10.1002/jnr.21678
110.
Korshunova I. Novitskaya V. Kiryushko D. Pedersen N. Kolkova K. Kropotova E. (2007 ). GAP-43 regulates NCAM-180-mediated neurite outgrowth. J. Neurochem. 100 1599–1612.
Not in our library10.1111/j.1471-4159.2006.04316.x
111.
Selective rab11 transport and the intrinsic regenerative ability of CNS axons · 2017
Not checked
112.
Kossmann T. Hans V. Imhof H. G. Trentz O. Morganti-Kossmann M. C. (1996 ). Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 713 143–152.
Not in our library10.1016/0006-8993(95)01501-9
113.
Kossmann T. Hans V. H. Imhof H. G. Stocker R. Grob P. Trentz O. (1995 ). Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock 4 311–317.
Not in our library10.1097/00024382-199511000-00001
114.
Kuchibhotla K. V. Goldman S. T. Lattarulo C. R. Wu H.-Y. Hyman B. T. Bacskai B. J. (2008 ). Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59 214–225.
Not in our library10.1016/j.neuron.2008.06.008
115.
Laux T. Fukami K. Thelen M. Golub T. Frey D. Caroni P. (2000 ). GAP43, MARCKS, and CAP23 modulate PI(4,5)P(2) at plasmalemmal rafts, and regulate cell cortex actin dynamics through a common mechanism. J. Cell Biol. 149 1455–1472.
Not in our library10.1083/jcb.149.7.1455
116.
Lee S. B. Bagley J. A. Lee H. Y. Jan L. Y. Jan Y.-N. (2011 ). Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila. Proc. Natl. Acad. Sci. U.S.A. 108 16795–16800.
Not in our library10.1073/pnas.1113573108
117.
Leshchyns’ka I. Sytnyk V. Morrow J. S. Schachner M. (2003 ). Neural cell adhesion molecule (NCAM) association with PKCbeta2 via betaI spectrin is implicated in NCAM-mediated neurite outgrowth. J. Cell Biol. 161 625–639.
Not in our library10.1083/jcb.200303020
118.
Li C. Sun Y. Yang W. Ma S. Zhang L. Zhao J. (2019a ). Pilose Antler Extracts (PAEs) protect against neurodegeneration in 6-OHDA-Induced Parkinson’s Disease Rat Models. Evid. Based. Complement. Altern. Med. 2019:7276407.
Not in our library10.1155/2019/7276407
119.
Li J. Jia Z. Xu W. Guo W. Zhang M. Bi J. (2019b ). TGN-020 alleviates edema and inhibits astrocyte activation and glial scar formation after spinal cord compression injury in rats. Life Sci. 222 148–157.
Not in our library10.1016/j.lfs.2019.03.007
120.
Li P. Banjade S. Cheng H.-C. Kim S. Chen B. Guo L. (2012 ). Phase transitions in the assembly of multivalent signalling proteins. Nature 483 336–340.
Not in our library10.1038/nature10879
121.
Liang X. Lu Y. Neubert T. A. Resh M. D. (2002 ). Mass spectrometric analysis of GAP-43/neuromodulin reveals the presence of a variety of fatty acylated species. J. Biol. Chem. 277 33032–33040.
Not in our library10.1074/jbc.m204607200
122.
IL-10 Protects Neurites in Oxygen-Glucose-Deprived Cortical Neurons through the PI3K/Akt Pathway. · 2015
Not checked
123.
Liu S.-J. Gasperini R. Foa L. Small D. H. (2010 ). Amyloid-beta decreases cell-surface AMPA receptors by increasing intracellular calcium and phosphorylation of GluR2. J. Alzheimers Dis. 21 655–666.
Not in our library10.3233/jad-2010-091654
124.
Liu Y. C. Storm D. R. (1989 ). Dephosphorylation of neuromodulin by calcineurin. J. Biol. Chem. 264 12800–12804.
Not in our library
125.
Lovinger D. M. Colley P. A. Akers R. F. Nelson R. B. Routtenberg A. (1986 ). Direct relation of long-term synaptic potentiation to phosphorylation of membrane protein F1, a substrate for membrane protein kinase C. Brain Res. 399 205–211.
Not in our library10.1016/0006-8993(86)91510-6
126.
Maekawa S. Maekawa M. Hattori S. Nakamura S. (1993 ). Purification and molecular cloning of a novel acidic calmodulin binding protein from rat brain. J. Biol. Chem. 268 13703–13709.
Not in our library
127.
Maekawa S. Murofushi H. Nakamura S. (1994 ). Inhibitory effect of calmodulin on phosphorylation of NAP-22 with protein kinase C. J. Biol. Chem. 269 19462–19465.
Not in our library
128.
Disrupted cortical map and absence of cortical barrels in growth-associated protein (GAP)-43 knockout mice · 1999
Not checked
129.
Masliah E. (1995 ). Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol. Histopathol. 10 509–519.
Not in our library
130.
Masliah E. Mallory M. Hansen L. Alford M. Albright T. Deteresa R. (1991 ). Patterns of aberrant sprouting in Alzheimer’s disease. Neuron 6 729–739.
Not in our library10.1016/0896-6273(91)90170-5
131.
Mason M. (2002 ). Transcriptional upregulation of SCG10 and CAP-23 Is correlated with regeneration of the axons of peripheral and central neurons in Vivo. Mol. Cell. Neurosci. 20 595–615.
Not in our library10.1006/mcne.2002.1140
132.
Masters C. L. Simms G. Weinman N. A. Multhaup G. Mcdonald B. L. Beyreuther K. (1985 ). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U.S.A. 82 4245–4249.
Not in our library10.1073/pnas.82.12.4245
133.
Matsubara M. Nakatsu T. Kato H. Taniguchi H. (2004 ). Crystal structure of a myristoylated CAP-23/NAP-22 N-terminal domain complexed with Ca2+/calmodulin. EMBO J. 23 712–718.
Not in our library10.1038/sj.emboj.7600093
134.
Matsuda W. Furuta T. Nakamura K. C. Hioki H. Fujiyama F. Arai R. (2009 ). Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29 444–453.
Not in our library10.1523/jneurosci.4029-08.2009
135.
Matsushima H. Shimohama S. Chachin M. Taniguchi T. Kimura J. (1996 ). Ca2+-dependent and Ca2+-independent protein kinase C changes in the brain of patients with Alzheimer’s disease. J. Neurochem. 67 317–323.
Not in our library10.1046/j.1471-4159.1996.67010317.x
136.
McGuire C. B. Snipes G. J. Norden J. J. (1988 ). Light-microscopic immunolocalization of the growth- and plasticity-associated protein GAP-43 in the developing rat brain. Brain Res. 469 277–291.
Not in our library10.1016/0165-3806(88)90189-7
137.
McLaughlin R. E. Denny J. B. (1999 ). Palmitoylation of GAP-43 by the ER-Golgi intermediate compartment and Golgi apparatus. Biochim. Biophys. Acta 1451 82–92.
Not in our library10.1016/s0167-4889(99)00074-9
138.
Meiri K. F. Pfenninger K. H. Willard M. B. (1986 ). Growth-associated protein, GAP-43, a polypeptide that is induced when neurons extend axons, is a component of growth cones and corresponds to pp46, a major polypeptide of a subcellular fraction enriched in growth cones. Proc. Natl. Acad. Sci. U.S.A. 83 3537–3541.
Not in our library10.1073/pnas.83.10.3537
139.
Metz G. A. Schwab M. E. (2004 ). Behavioral characterization in a comprehensive mouse test battery reveals motor and sensory impairments in growth-associated protein-43 null mutant mice. Neuroscience 129 563–574.
Not in our library10.1016/j.neuroscience.2004.07.053
140.
Miao Y. Tipakornsaowapak T. Zheng L. Mu Y. Lewellyn E. (2018 ). Phospho-regulation of intrinsically disordered proteins for actin assembly and endocytosis. FEBS J. 285 2762–2784.
Not in our library10.1111/febs.14493
141.
Miyake K. Yamamoto W. Tadokoro M. Takagi N. Sasakawa K. Nitta A. (2002 ). Alterations in hippocampal GAP-43, BDNF, and L1 following sustained cerebral ischemia. Brain Res. 935 24–31.
Not in our library10.1016/s0006-8993(02)02420-4
142.
Mohammad H. M. F. Sami M. M. Makary S. Toraih E. A. Mohamed A. O. El-Ghaiesh S. H. (2019 ). Neuroprotective effect of levetiracetam in mouse diabetic retinopathy: effect on glucose transporter-1 and GAP43 expression. Life Sci. 232:116588.
Not in our library10.1016/j.lfs.2019.116588
143.
Morganti-Kossman M. C. Lenzlinger P. M. Hans V. Stahel P. Csuka E. Ammann E. (1997 ). Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue. Mol. Psychiatry 2 133–136.
Not in our library10.1038/sj.mp.4000227
144.
Morrison J. H. Hof P. R. (2002 ). Selective vulnerability of corticocortical and hippocampal circuits in aging and Alzheimer’s disease. Prog. Brain Res. 136 467–486.
Not in our library10.1016/s0079-6123(02)36039-4
145.
Mosevitsky M. Silicheva I. (2011 ). Subcellular and regional location of “brain” proteins BASP1 and MARCKS in kidney and testis. Acta Histochem. 113 13–18.
Not in our library10.1016/j.acthis.2009.07.002
146.
Mosevitsky M. I. (2005 ). “Nerve ending “signal” proteins GAP-43, MARCKS, and BASP1. Int. Rev. Cytol. 245 245–325.
Not in our library10.1016/s0074-7696(05)45007-x
147.
Mosevitsky M. I. Capony J. P. Gyu S. Novitskaya V. A. Ayu P. Zakharov V. V. (1997 ). The BASP1 family of myristoylated proteins abundant in axonal termini. Primary structure analysis and physico-chemical properties. Biochimie 79 373–384.
Not in our library10.1016/s0300-9084(97)80032-6
148.
Mosevitsky M. I. Novitskaya V. A. Ayu P. Gyu S. (1994 ). Neuronal protein GAP-43 is a member of novel group of brain acid-soluble proteins (BASPs). Neurosci. Res. 19 223–228.
Not in our library10.1016/0168-0102(94)90146-5
149.
Mulkey R. M. Endo S. Shenolikar S. Malenka R. C. (1994 ). Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369 486–488.
Not in our library10.1038/369486a0
150.
Munsie L. N. Truant R. (2012 ). The role of the cofilin-actin rod stress response in neurodegenerative diseases uncovers potential new drug targets. BioArchitecture 2 204–208.
Not in our library10.4161/bioa.22549
151.
Musunuri S. Wetterhall M. Ingelsson M. Lannfelt L. Artemenko K. Bergquist J. (2014 ). Quantification of the brain proteome in Alzheimer’s disease using multiplexed mass spectrometry. J. Proteome Res. 13 2056–2068.
Not in our library10.1021/pr401202d
152.
Nedivi E. Basi G. S. Akey I. V. Skene J. H. (1992 ). A neural-specific GAP-43 core promoter located between unusual DNA elements that interact to regulate its activity. J. Neurosci. 12 691–704.
Not in our library10.1523/jneurosci.12-03-00691.1992
153.
Neve R. L. Coopersmith R. Mcphie D. L. Santeufemio C. Pratt K. G. Murphy C. J. (1998 ). The neuronal growth-associated protein GAP-43 interacts with rabaptin-5 and participates in endocytosis. J. Neurosci. 18 7757–7767.
Not in our library10.1523/jneurosci.18-19-07757.1998
154.
Neve R. L. Finch E. A. Bird E. D. Benowitz L. I. (1988 ). Growth-associated protein GAP-43 is expressed selectively in associative regions of the adult human brain. Proc. Natl. Acad. Sci. U.S.A. 85 3638–3642.
Not in our library10.1073/pnas.85.10.3638
155.
Nguyen T. L. X. Kim C. K. Cho J.-H. Lee K.-H. Ahn J.-Y. (2010 ). Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7/IGF-IR [corrected]. Exp. Mol. Med. 42 583–595.
Not in our library10.3858/emm.2010.42.8.060
156.
Noureddine M. A. Qin X.-J. Oliveira S. A. Skelly T. J. Van Der Walt J. Hauser M. A. (2005 ). Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease. Hum. Genet. 117 27–33.
Not in our library10.1007/s00439-005-1259-2
157.
O’Neil K. T. DeGrado W. F. (1990 ). How calmodulin binds its targets: sequence independent recognition of amphiphilic alpha-helices. Trends Biochem. Sci. 15 59–64.
Not in our library10.1016/0968-0004(90)90177-d
158.
Pacelli C. Giguere N. Bourque M. J. Levesque M. Slack R. S. Trudeau L. E. (2015 ). Elevated mitochondrial bioenergetics and axonal arborization size are key contributors to the vulnerability of dopamine neurons. Curr. Biol. 25 2349–2360.
Not in our library10.1016/j.cub.2015.07.050
159.
BDNF as a Promising Therapeutic Agent in Parkinson’s Disease · 2020
No notice
160.
Pang Z. P. Cao P. Xu W. Südhof T. C. (2010 ). Calmodulin controls synaptic strength via presynaptic activation of calmodulin kinase II. J. Neurosci. 30 4132–4142.
Not in our library10.1523/jneurosci.3129-09.2010
161.
Parhad I. M. Oishi R. Clark A. W. (1992 ). GAP-43 gene expression is increased in anterior horn cells of amyotrophic lateral sclerosis. Ann. Neurol. 31 593–597.
Not in our library10.1002/ana.410310605
162.
Pascale A. Gusev P. A. Amadio M. Dottorini T. Govoni S. Alkon D. L. (2004 ). Increase of the RNA-binding protein HuD and posttranscriptional up-regulation of the GAP-43 gene during spatial memory. Proc. Natl. Acad. Sci. U.S.A. 101 1217–1222.
Not in our library10.1073/pnas.0307674100
163.
Patel N. K. Pavese N. Javed S. Hotton G. R. Brooks D. J. Gill S. S. (2013 ). Benefits of putaminal GDNF infusion in Parkinson disease are maintained after GDNF cessation. Neurology 81 1176–1178.
Not in our library10.1212/wnl.0b013e3182a55ea5
164.
Patterson S. I. Skene J. H. (1999 ). A shift in protein S-palmitoylation, with persistence of growth-associated substrates, marks a critical period for synaptic plasticity in developing brain. J. Neurobiol. 39 423–437.
Not in our library10.1002/(sici)1097-4695(19990605)39:3<423::aid-neu8>3.0.co;2-z
165.
Perrone-Bizzozero N. I. Cansino V. V. Kohn D. T. (1993 ). Posttranscriptional regulation of GAP-43 gene expression in PC12 cells through protein kinase C-dependent stabilization of the mRNA. J. Cell Biol. 120 1263–1270.
Not in our library10.1083/jcb.120.5.1263
166.
Perrone-Bizzozero N. I. Neve R. L. Irwin N. Lewis S. Fischer I. Benowitz L. I. (1991 ). Post-transcriptional regulation of GAP-43 mRNA levels during neuronal differentiation and nerve regeneration. Mol. Cell. Neurosci. 2 402–409.
Not in our library10.1016/1044-7431(91)90027-l
167.
A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation · 2018
No notice
168.
Phinney A. L. Deller T. Stalder M. Calhoun M. E. Frotscher M. Sommer B. (1999 ). Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice. J. Neurosci. 19 8552–8559.
Not in our library10.1523/jneurosci.19-19-08552.1999
169.
Qi D. Ouyang C. Wang Y. Zhang S. Ma X. Song Y. (2014 ). HO-1 attenuates hippocampal neurons injury via the activation of BDNF-TrkB-PI3K/Akt signaling pathway in stroke. Brain Res. 1577 69–76.
Not in our library10.1016/j.brainres.2014.06.031
170.
Quattrone A. Pascale A. Nogues X. Zhao W. Gusev P. Pacini A. (2001 ). Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA-stabilizing proteins. Proc. Natl. Acad. Sci. U.S.A. 98 11668–11673.
Not in our library10.1073/pnas.191388398
171.
Rechsteiner M. Rogers S. W. (1996 ). PEST sequences and regulation by proteolysis. Trends Biochem. Sci. 21 267–271.
Not in our library10.1016/s0968-0004(96)10031-1
172.
Rekart J. L. Meiri K. Routtenberg A. (2005 ). Hippocampal-dependent memory is impaired in heterozygous GAP-43 knockout mice. Hippocampus 15 1–7.
Not in our library10.1002/hipo.20045
173.
Rekart J. L. Quinn B. Mesulam M. M. Routtenberg A. (2004 ). Subfield-specific increase in brain growth protein in postmortem hippocampus of Alzheimer’s patients. Neuroscience 126 579–584.
Not in our library10.1016/j.neuroscience.2004.03.060
174.
Riederer B. M. Routtenberg A. (1999 ). Can GAP-43 interact with brain spectrin? Brain Res. Mol. Brain Res. 71 345–348.
Not in our library10.1016/s0169-328x(99)00179-5
175.
Rostami E. Krueger F. Plantman S. Davidsson J. Agoston D. Grafman J. (2014 ). Alteration in BDNF and its receptors, full-length and truncated TrkB and p75(NTR) following penetrating traumatic brain injury. Brain Res. 1542 195–205.
Not in our library10.1016/j.brainres.2013.10.047
176.
Routtenberg A. Lovinger D. M. (1985 ). Selective increase in phosphorylation of a 47-kDa protein (F1) directly related to long-term potentiation. Behav. Neural Biol. 43 3–11.
Not in our library10.1016/s0163-1047(85)91426-8
177.
Saal K.-A. Galter D. Roeber S. Bähr M. Tönges L. Lingor P. (2017 ). Altered expression of growth associated protein-43 and Rho kinase in human patients with Parkinson’s disease. Brain Pathol. 27 13–25.
Not in our library10.1111/bpa.12346
178.
Sandelius Å Sandgren S. Axelsson M. Malmeström C. Novakova L. Kostanjevecki V. (2019 ). Cerebrospinal fluid growth-associated protein 43 in multiple sclerosis. Sci. Rep. 9:17309.
Not in our library10.1038/s41598-019-54032-1
179.
Sanna M. D. Quattrone A. Ghelardini C. Galeotti N. (2014 ). PKC-mediated HuD-GAP43 pathway activation in a mouse model of antiretroviral painful neuropathy. Pharmacol. Res. 81 44–53.
Not in our library10.1016/j.phrs.2014.02.004
180.
Sechi A. S. Wehland J. (2000 ). The actin cytoskeleton and plasma membrane connection: PtdIns(4,5)P(2) influences cytoskeletal protein activity at the plasma membrane. J. Cell Sci. 113(Pt 21), 3685–3695.
Not in our library10.1242/jcs.113.21.3685
181.
Shen Y. Mani S. Donovan S. L. Schwob J. E. Meiri K. F. (2002 ). Growth-associated protein-43 is required for commissural axon guidance in the developing vertebrate nervous system. J. Neurosci. 22 239–247.
Not in our library10.1523/jneurosci.22-01-00239.2002
182.
Silver J. Miller J. H. (2004 ). Regeneration beyond the glial scar. Nat. Rev. Neurosci. 5 146–156.
Not in our library10.1038/nrn1326
183.
Sjogren M. Minthon L. Davidsson P. Granerus A. K. Clarberg A. Vanderstichele H. (2000 ). CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging. J. Neural Transm. 107 563–579.
Not in our library10.1007/s007020070079
184.
Skene J. H. (1989 ). Axonal growth-associated proteins. Annu. Rev. Neurosci. 12 127–156.
Not in our library10.1146/annurev.ne.12.030189.001015
185.
Skene J. H. Jacobson R. D. Snipes G. J. Mcguire C. B. Norden J. J. Freeman J. A. (1986 ). A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes. Science 233 783–786.
Not in our library10.1126/science.3738509
186.
Skene J. H. Virág I. (1989 ). Posttranslational membrane attachment and dynamic fatty acylation of a neuronal growth cone protein, GAP-43. J. Cell Biol. 108 613–624.
Not in our library10.1083/jcb.108.2.613
187.
Skene J. H. Willard M. (1981 ). Changes in axonally transported proteins during axon regeneration in toad retinal ganglion cells. J. Cell Biol. 89 86–95.
Not in our library10.1083/jcb.89.1.86
188.
Smythe E. Ayscough K. R. (2006 ). Actin regulation in endocytosis. J. Cell Sci. 119 4589–4598.
Not in our library10.1242/jcs.03247
189.
Spencer S. A. Schuh S. M. Liu W. S. Willard M. B. (1992 ). GAP-43, a protein associated with axon growth, is phosphorylated at three sites in cultured neurons and rat brain. J. Biol. Chem. 267 9059–9064.
Not in our library
190.
Spillantini M. G. Schmidt M. L. Lee V. M. Trojanowski J. Q. Jakes R. Goedert M. (1997 ). Alpha-synuclein in Lewy bodies. Nature 388 839–840.
Not in our library10.1038/42166
191.
Strittmatter S. M. Fankhauser C. Huang P. L. Mashimo H. Fishman M. C. (1995 ). Neuronal pathfinding is abnormal in mice lacking the neuronal growth cone protein GAP-43. Cell 80 445–452.
Not in our library10.1016/0092-8674(95)90495-6
192.
Strittmatter S. M. Igarashi M. Fishman M. C. (1994 ). GAP-43 amino terminal peptides modulate growth cone morphology and neurite outgrowth. J. Neurosci. 14 5503–5513.
Not in our library10.1523/jneurosci.14-09-05503.1994
193.
Sudo Y. Valenzuela D. Beck-Sickinger A. G. Fishman M. C. Strittmatter S. M. (1992 ). Palmitoylation alters protein activity: blockade of G(o) stimulation by GAP-43. EMBO J. 11 2095–2102.
Not in our library10.1002/j.1460-2075.1992.tb05268.x
194.
Sun M.-K. Alkon D. L. (2014 ). The “Memory Kinases”: roles of pkc isoforms in signal processing and memory formation. Prog. Mol. Biol. Transl. Sci. 122 31–59.
Not in our library10.1016/b978-0-12-420170-5.00002-7
195.
Sun Y. Leong N. T. Jiang T. Tangara A. Darzacq X. Drubin D. G. (2017 ). Switch-like Arp2/3 activation upon WASP and WIP recruitment to an apparent threshold level by multivalent linker proteins in vivo. eLife 6:e29140.
Not in our library10.7554/elife.29140
196.
Tagawa K. Homma H. Saito A. Fujita K. Chen X. Imoto S. (2015 ). Comprehensive phosphoproteome analysis unravels the core signaling network that initiates the earliest synapse pathology in preclinical Alzheimer’s disease brain. Hum. Mol. Genet. 24 540–558.
Not in our library10.1093/hmg/ddu475
197.
Takasaki A. Hayashi N. Matsubara M. Yamauchi E. Taniguchi H. (1999 ). Identification of the calmodulin-binding domain of neuron-specific protein kinase C substrate protein CAP-22/NAP-22. Direct involvement of protein myristoylation in calmodulin-target protein interaction. J. Biol. Chem. 274 11848–11853.
Not in our library10.1074/jbc.274.17.11848
198.
Tejero-Díez P. Rodríguez-Sánchez P. Martín-Cófreces N. B. Díez-Guerra F. J. (2000 ). bFGF stimulates GAP-43 phosphorylation at ser41 and modifies its intracellular localization in cultured hippocampal neurons. Mol. Cell. Neurosci. 16 766–780.
Not in our library10.1006/mcne.2000.0915
199.
Teravskis P. J. Covelo A. Miller E. C. Singh B. Martell-Martínez H. A. Benneyworth M. A. (2018 ). A53T mutant alpha-synuclein induces Tau-dependent postsynaptic impairment independently of neurodegenerative changes. J. Neurosci. 38 9754–9767.
Not in our library10.1523/jneurosci.0344-18.2018
200.
Tompa P. Fuxreiter M. (2008 ). Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem. Sci. 33 2–8.
Not in our library10.1016/j.tibs.2007.10.003
201.
Tonges L. Szego E. M. Hause P. Saal K. A. Tatenhorst L. Koch J. C. (2014 ). Alpha-synuclein mutations impair axonal regeneration in models of Parkinson’s disease. Front. Aging Neurosci. 6:239
Not in our library10.3389/fnagi.2014.00239
202.
Tron C. Lemaitre F. Verstuyft C. Petitcollin A. Verdier M. C. Bellissant E. (2019 ). Pharmacogenetics of membrane transporters of tacrolimus in solid organ transplantation. Clin. Pharmacokinet. 58 593–613.
Not in our library10.1007/s40262-018-0717-7
203.
Tsai K. C. Cansino V. V. Kohn D. T. Neve R. L. Perrone-Bizzozero N. I. (1997 ). Post-transcriptional regulation of the GAP-43 gene by specific sequences in the 3′ untranslated region of the mRNA. J. Neurosci. 17 1950–1958.
Not in our library10.1523/jneurosci.17-06-01950.1997
204.
Tysnes O.-B. Storstein A. (2017 ). Epidemiology of Parkinson’s disease. J. Neural Transm. 124 901–905.
Not in our library10.1007/s00702-017-1686-y
205.
Udvadia A. J. Köster R. W. Skene J. H. (2001 ). GAP-43 promoter elements in transgenic zebrafish reveal a difference in signals for axon growth during CNS development and regeneration. Development 128 1175–1182.
Not in our library10.1242/dev.128.7.1175
206.
Uzumcu A. Candan S. Toksoy G. Uyguner Z. O. Karaman B. Eris H. (2009 ). Mutational screening of BASP1 and transcribed processed pseudogene TPPsig-BASP1 in patients with Möbius syndrome. J. Genet. Genomics 36 251–256.
Not in our library10.1016/s1673-8527(08)60112-5
207.
Wang H. Y. Pisano M. R. Friedman E. (1994 ). Attenuated protein kinase C activity and translocation in Alzheimer’s disease brain. Neurobiol. Aging 15 293–298.
Not in our library10.1016/0197-4580(94)90023-x
208.
Wang M. J. Jiang L. Chen H. S. Cheng L. (2019a ). Levetiracetam protects against cognitive impairment of subthreshold convulsant discharge model rats by activating protein kinase C (PKC)-Growth-Associated Protein 43 (GAP-43)-Calmodulin-Dependent Protein Kinase (CaMK) Signal Transduction Pathway. Med. Sci. Monit. 25 4627–4638.
Not in our library10.12659/msm.913542
209.
Wang Q. Zhang Y. Wang M. Song W.-M. Shen Q. Mckenzie A. (2019b ). The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease. Nat. Commun. 10:5234.
Not in our library10.1038/s41467-019-13144-y
210.
Weber J. R. Skene J. H. (1997 ). Identification of a novel repressive element that contributes to neuron-specific gene expression. J. Neurosci. 17 7583–7593.
Not in our library10.1523/jneurosci.17-20-07583.1997
211.
Wegmann S. Eftekharzadeh B. Tepper K. Zoltowska K. M. Bennett R. E. Dujardin S. (2018 ). Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J. 37:e98049.
Not in our library10.15252/embj.201798049
212.
Wetmore C. Olson L. Bean A. J. (1994 ). Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors. J. Neurosci. 14 1688–1700.
Not in our library10.1523/jneurosci.14-03-01688.1994
213.
Whitehouse P. J. Price D. L. Struble R. G. Clark A. W. Coyle J. T. Delon M. R. (1982 ). Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215 1237–1239.
Not in our library10.1126/science.7058341
214.
Widmer F. Caroni P. (1990 ). Identification, localization, and primary structure of CAP-23, a particle-bound cytosolic protein of early development. J. Cell Biol. 111 3035–3047.
Not in our library10.1083/jcb.111.6.3035
215.
Wiederkehr A. Staple J. Caroni P. (1997 ). The motility-associated proteins GAP-43, MARCKS, and CAP-23 share unique targeting and surface activity-inducing properties. Exp. Cell Res. 236 103–116.
Not in our library10.1006/excr.1997.3709
216.
Wu H. Lu D. Jiang H. Xiong Y. Qu C. Li B. (2008 ). Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J. Neurotrauma 25 130–139.
Not in our library10.1089/neu.2007.0369
217.
Xiao H.-S. Huang Q.-H. Zhang F.-X. Bao L. Lu Y.-J. Guo C. (2002 ). Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc. Natl. Acad. Sci. U.S.A. 99 8360–8365.
Not in our library10.1073/pnas.122231899
218.
Yamamoto Y. Sokawa Y. Maekawa S. (1997 ). Biochemical evidence for the presence of NAP-22, a novel acidic calmodulin binding protein, in the synaptic vesicles of rat brain. Neurosci. Lett. 224 127–130.
Not in our library10.1016/s0304-3940(97)13482-6
219.
Yang P. Qin Y. Bian C. Zhao Y. Zhang W. (2015 ). Intrathecal delivery of IL-6 reactivates the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex after spinal cord injury. PLoS One 10:e0127772.
Not in our library10.1371/journal.pone.0127772
220.
Yang P. Wen H. Ou S. Cui J. Fan D. (2012 ). IL-6 promotes regeneration and functional recovery after cortical spinal tract injury by reactivating intrinsic growth program of neurons and enhancing synapse formation. Exp. Neurol. 236 19–27.
Not in our library10.1016/j.expneurol.2012.03.019
221.
Zakharov V. V. Capony J.-P. Derancourt J. Kropolova E. S. Novitskaya V. A. Bogdanova M. N. (2003 ). Natural N-terminal fragments of brain abundant myristoylated protein BASP1. Biochim. Biophys. Acta 1622 14–19.
Not in our library10.1016/s0304-4165(03)00099-0
222.
Zakharov V. V. Mosevitsky M. I. (2007 ). M-calpain-mediated cleavage of GAP-43 near Ser41 is negatively regulated by protein kinase C, calmodulin and calpain-inhibiting fragment GAP-43-3. J. Neurochem. 101 1539–1551.
Not in our library10.1111/j.1471-4159.2007.04452.x
223.
Zakharov V. V. Mosevitsky M. I. (2010 ). Oligomeric structure of brain abundant proteins GAP-43 and BASP1. J. Struct. Biol. 170 470–483.
Not in our library10.1016/j.jsb.2010.01.010
224.
Zhang M. Vogel H. J. Zwiers H. (1994 ). Nuclear magnetic resonance studies of the structure of B50/neuromodulin and its interaction with calmodulin. Biochem. Cell Biol. 72 109–116.
Not in our library10.1139/o94-017

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.