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Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity.

Published version
Peer-reviewed

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Authors

Chappard, Alexandre  ORCID logo  https://orcid.org/0000-0002-9522-2575
Singh, Bhanu P 
Maclachlan, Catherine 
Rodrigues, Margarida 

Abstract

Aggregation of alpha-synuclein (α-Syn) drives Parkinson's disease (PD), although the initial stages of self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked the intracellular conformational states of α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, and we show here that α-Syn converts from a monomeric state into two distinct oligomeric states in neurons in a concentration-dependent and sequence-specific manner. Three-dimensional FRET-correlative light and electron microscopy (FRET-CLEM) revealed that intracellular seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The mitochondrial lipid cardiolipin triggers rapid oligomerization of A53T α-Syn, and cardiolipin is sequestered within aggregating lipid-protein complexes. Mitochondrial aggregates impair complex I activity and increase mitochondrial reactive oxygen species (ROS) generation, which accelerates the oligomerization of A53T α-Syn and causes permeabilization of mitochondrial membranes and cell death. These processes were also observed in induced pluripotent stem cell (iPSC)-derived neurons harboring A53T mutations from patients with PD. Our study highlights a mechanism of de novo α-Syn oligomerization at mitochondrial membranes and subsequent neuronal toxicity.

Description

Keywords

Article, /631/378/1689/1718, /631/57, /631/80/642/333, article

Journal Title

Nat Neurosci

Conference Name

Journal ISSN

1097-6256
1546-1726

Volume Title

25

Publisher

Springer Science and Business Media LLC
Sponsorship
RCUK | Engineering and Physical Sciences Research Council (EPSRC) (EP/L016559/1, EP/L016559/1)
Government Council on Grants, Russian Federation (075-15-2019-1877)
RCUK | Medical Research Council (MRC) (MR/T008199/1, MR/T008199/1)
Alzheimer’s Research UK (ARUK) (ARUK-EG2018B-004))
Wellcome Trust (Wellcome) (WT089698)