Modeling Parkinson's disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines

被引：18

作者：

Bayati, Armin ^{[1
]}

Ayoubi, Riham ^{[1
]}

Aguila, Adriana ^{[1
]}

Zorca, Cornelia E. ^{[1
]}

Deyab, Ghislaine ^{[1
]}

Han, Chanshuai ^{[2
]}

Recinto, Sherilyn Junelle ^{[1
]}

Nguyen-Renou, Emmanuelle ^{[2
]}

Rocha, Cecilia ^{[2
]}

Maussion, Gilles ^{[2
]}

Luo, Wen ^{[2
]}

Shlaifer, Irina ^{[2
]}

Banks, Emily ^{[1
]}

Mcdowell, Ian ^{[1
]}

Del Cid Pellitero, Esther ^{[1
]}

Ding, Xue Er ^{[3
]}

Sharif, Behrang ^{[1
]}

Seguela, Philippe ^{[1
]}

Yaqubi, Moein ^{[1
]}

Chen, Carol X. -Q. ^{[2
]}

You, Zhipeng ^{[2
]}

Abdian, Narges ^{[2
]}

Mcbride, Heidi M. ^{[1
]}

Fon, Edward A. ^{[1
]}

Stratton, Jo Anne ^{[1
]}

Durcan, Thomas M. ^{[2
]}

Nahirney, Patrick C. ^{[4
]}

Mcpherson, Peter S. ^{[1
]}

机构：

[1] McGill Univ, Montreal Neurol Inst, Dept Neurol & Neurosurg, Montreal, PQ, Canada

[2] McGill Univ, Neuros Early Drug Discovery Unit EDDU, Montreal, PQ, Canada

[3] Carnegie Mellon Univ, Computat Biol Dept, Pittsburgh, PA USA

[4] Univ Victoria, Div Med Sci, Victoria, BC, Canada

来源：

NATURE NEUROSCIENCE | 2024年 / 27卷 / 12期

基金：

加拿大健康研究院;

关键词：

LEWY BODY; INTERFERON-GAMMA; IFN-GAMMA; GLUCOCEREBROSIDASE MUTATIONS; LYSOSOME BIOGENESIS; LAMP PROTEINS; IN-VITRO; BODIES; AGGREGATION; MICROGLIA;

D O I：

10.1038/s41593-024-01775-4

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Lewy bodies (LBs), alpha-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with alpha-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-gamma or interleukin-1 beta treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-gamma impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology.

引用

页码：2401 / 2416

页数：47

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