TY - JOUR
T1 - Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity
AU - Choi, Minee L.
AU - Chappard, Alexandre
AU - Singh, Bhanu P.
AU - Maclachlan, Catherine
AU - Rodrigues, Margarida
AU - Fedotova, Evgeniya I.
AU - Berezhnov, Alexey V.
AU - De, Suman
AU - Peddie, Christopher J.
AU - Athauda, Dilan
AU - Virdi, Gurvir S.
AU - Zhang, Weijia
AU - Evans, James R.
AU - Wernick, Anna I.
AU - Zanjani, Zeinab Shadman
AU - Angelova, Plamena R.
AU - Esteras, Noemi
AU - Vinokurov, Andrey Y.
AU - Morris, Katie
AU - Jeacock, Kiani
AU - Tosatto, Laura
AU - Little, Daniel
AU - Gissen, Paul
AU - Clarke, David J.
AU - Kunath, Tilo
AU - Collinson, Lucy
AU - Klenerman, David
AU - Abramov, Andrey Y.
AU - Horrocks, Mathew H.
AU - Gandhi, Sonia
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137745367&partnerID=8YFLogxK
U2 - 10.1038/s41593-022-01140-3
DO - 10.1038/s41593-022-01140-3
M3 - Article
C2 - 36042314
AN - SCOPUS:85137745367
SN - 1097-6256
VL - 25
SP - 1134
EP - 1148
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 9
ER -