| Title: |
Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. |
| Authors: |
Choi, Minee L; Chappard, Alexandre; Singh, Bhanu P; Maclachlan, Catherine; Rodrigues, Margarida; Fedotova, Evgeniya I; Berezhnov, Alexey V; De, Suman; Peddie, Christopher J; Athauda, Dilan; Virdi, Gurvir S; Zhang, Weijia; Evans, James R; Wernick, Anna I; Zanjani, Zeinab Shadman; Angelova, Plamena R; Esteras, Noemi; Vinokurov, Andrey Y; Morris, Katie; Jeacock, Kiani; Tosatto, Laura; Little, Daniel; Gissen, Paul; Clarke, David J; Kunath, Tilo; Collinson, Lucy; Klenerman, David; Abramov, Andrey Y; Horrocks, Mathew H; Gandhi, Sonia |
| Source: |
essn: 1546-1726 ; nlmid: 9809671 |
| Publication Year: |
2022 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Neurons; Mitochondria; Humans; Parkinson Disease; Cardiolipins; Mitochondrial Membranes; alpha-Synuclein |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
PMC9448679; https://www.repository.cam.ac.uk/handle/1810/341570 |
| DOI: |
10.17863/CAM.88995 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/341570; https://doi.org/10.17863/CAM.88995 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.DF8F2CE0 |
| Database: |
BASE |