Structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Choi, M. L.; Chappard, A.; Singh, B. P.; Maclachlan, C.; Rodrigues, M.; Fedotova, E.; Berezhnov, A.; De, S.; Peddie, C.; Athauda, D.; Virdi, G. S.; Zhang, W.; Evans, J. R.; Wernick, A.; Zanjani, Z.; Angelova, P. R.; Esteras, N.; Andrey, A.; Morris, K.; Jeacock, K.; Tosatto, L.; Little, D.; Gissen, P.; Collinson, L.; Clarke, D. J.; Kunath, T.; Klenerman, D.; Abramov, A. Y.; Horrocks, M. H.; Gandhi, S.

doi:10.1101/2022.06.07.494932

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bioRxiv · 10.1101/2022.06.07.494932

Structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

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Abstract

Aggregation of -Synuclein (-Syn) drives Parkinsons disease, although the initial stages of self-assembly and structural conversion have not been captured inside neurons. We track the intracellular conformational states of -Syn utilizing a single-molecule FRET biosensor, and show that -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 -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 -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.

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Choi, M. L., Chappard, A., Singh, B. P., Maclachlan, C., Rodrigues, M., Fedotova, E., Berezhnov, A., De, S., Peddie, C., Athauda, D., Virdi, G. S., Zhang, W., Evans, J. R., Wernick, A., Zanjani, Z., Angelova, P. R., Esteras, N., Andrey, A., Morris, K., Jeacock, K., Tosatto, L., Little, D., Gissen, P., Collinson, L., Clarke, D. J., Kunath, T., Klenerman, D., Abramov, A. Y., Horrocks, M. H., Gandhi, S.. 2022-06-09. Structural conversion of α-synuclein at the mitochondria induces neuronal toxicity. https://doi.org/10.1101/2022.06.07.494932

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