当前位置： SCI文献检索 > Stem Cell Reports期刊下所有文献 > ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.

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

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.

journal_name

Stem Cell Reports

journal_title

Stem cell reports

authors

Fernandes HJ,Hartfield EM,Christian HC,Emmanoulidou E,Zheng Y,Booth H,Bogetofte H,Lang C,Ryan BJ,Sardi SP,Badger J,Vowles J,Evetts S,Tofaris GK,Vekrellis K,Talbot K,Hu MT,James W,Cowley SA,Wade-Martins R

doi

10.1016/j.stemcr.2016.01.013

subject

Has Abstract

pub_date

2016-03-08 00:00:00

pages

342-56

issue

3

issn

2213-6711

pii

S2213-6711(16)00030-8

journal_volume

6

pub_type

杂志文章

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