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

ABSTRACT: Aggregation of alpha-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 Förster resonance energy transfer (smFRET) 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-Correlative light and electron microscopy (FRET- CLEM) reveals the structural organization and location of aggregation hotspots inside the neuron. Notably, multiple intracellular seeding events occur preferentially on membrane surfaces, especially at the 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 α-Syn 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.

ORGANISM(S): hiPSC derived neurons

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PROVIDER: S-BIAD465 | bioimages |

REPOSITORIES: bioimages

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