ER stress and autophagic perturbations lead to elevated extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-derived dopamine neurons

Journal article

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. In this article, Wade-Martins and colleagues show that in dopamine neurons from Parkinson's disease patients, the GBA-N370S mutation leads to the misprocessing of GCase, increased ER stress, and abnormal lipid profiles. Further, the GBA-N370S mutation impairs autophagic and lysosomal function, ultimately leading to increased α-synuclein release in dopaminergic neuronal cultures, which may be central in the early pathogenesis of Parkinson's disease.

Authors: Fernandes, H; Hartfield, E; Christian, H; Emmanoulidou, E; Zheng, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Stem Cell Reports
• Volume: 6
• Issue: 3
• Pages: 342-356
• Publication date: 2016-03-08
• Acceptance date: 2016-01-18
• DOI: 10.1016/j.stemcr.2016.01.013
• ISSN: 2213-6711