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ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons

Hugo J.R. Fernandes, Elizabeth M. Hartfield, Helen C. Christian and 17 more

Stem Cell Reports · 2016 · CC BY-NC-ND

doi:10.1016/j.stemcr.2016.01.013

Abstract

Heterozygous mutations in the glucocerebrosidase gene (GBA) represent the strongest common genetic risk factor for Parkinson's disease (PD), the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC) lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles. Furthermore, we observed autophagic perturbations and an enlargement of the lysosomal compartment specifically in dopamine neurons. Finally, we found increased extracellular α-synuclein in patient-derived neuronal culture medium, which was not associated with exosomes. Overall, ER stress, autophagic/lysosomal perturbations, and elevated extracellular α-synuclein likely represent critical early cellular phenotypes of PD, which might offer multiple therapeutic targets.

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Cited by papers we hold 15

GBA Variants and Parkinson Disease: Mechanisms and Treatments · 2022
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“LRRK2: Autophagy and Lysosomal Activity” · 2020
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Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells · 2020
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GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches · 2019
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Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons · 2019
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Glucocerebrosidase and its relevance to Parkinson disease · 2019
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Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes · 2019
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The genetic architecture of mitochondrial dysfunction in Parkinson’s disease · 2018
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LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages · 2018
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Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein · 2018
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The Endoplasmic Reticulum Unfolded Protein Response in Neurodegenerative Disorders and Its Potential Therapeutic Significance · 2017
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Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models · 2016
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A novel real time imaging platform to quantify macrophage phagocytosis · 2016
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C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia · 2016
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Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease · 2016
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