PT  - JOURNAL ARTICLE
AU  - Minee L. Choi
AU  - Alexandre Chappard
AU  - Bhanu P. Singh
AU  - Catherine Maclachlan
AU  - Margarida Rodrigues
AU  - Evgenia Fedotova
AU  - Alexey V. Berezhnov
AU  - Suman De
AU  - Chris Peddie
AU  - Dilan Athauda
AU  - Gurvir S. Virdi
AU  - Weijia Zhang
AU  - James R. Evans
AU  - Anna Wernick
AU  - Zeinab Shadman Zanjani
AU  - Plamena R. Angelova
AU  - Noemi Esteras
AU  - Andrey Vinikurov
AU  - Katie Morris
AU  - Kiani Jeacock
AU  - Laura Tosatto
AU  - Daniel Little
AU  - Paul Gissen
AU  - David J. Clarke
AU  - Tilo Kunath
AU  - Lucy Collinson
AU  - David Klenerman
AU  - Andrey Y. Abramov
AU  - Mathew H. Horrocks
AU  - Sonia Gandhi
TI  - Structural conversion of α-synuclein at the mitochondria induces neuronal toxicity
AID  - 10.1101/2022.06.07.494932
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.06.07.494932
4099  - http://biorxiv.org/content/early/2022/06/09/2022.06.07.494932.short
4100  - http://biorxiv.org/content/early/2022/06/09/2022.06.07.494932.full
AB  - Aggregation of α-Synuclein (α-Syn) drives Parkinson’s disease, although the initial stages of self-assembly and structural conversion have not been captured inside neurons. We track the intracellular conformational states of α-Syn utilizing a single-molecule FRET biosensor, and show that α-Syn converts from its monomeric state to form two distinct oligomeric states in neurons in a concentration dependent, and sequence specific manner. 3D FRET-CLEM reveals the structural organization, and location of aggregation hotspots inside the cell. Notably multiple intracellular seeding events occur preferentially on membrane surfaces, especially 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 ROS generation, which accelerates the oligomerization of A53T α-Syn, and ultimately causes permeabilization of mitochondrial membranes, and cell death. Patient iPSC derived neurons harboring A53T mutations exhibit accelerated oligomerization that is dependent on mitochondrial ROS, early mitochondrial permeabilization and neuronal death. Our study highlights a mechanism of de novo oligomerization at the mitochondria and its induction of neuronal toxicity.Competing Interest StatementThe authors have declared no competing interest.