α-synuclein fibrils per se but not α-synuclein seeded aggregation causes mitochondrial dysfunction and cell death in human neurons.

One of the major histopathological features of Parkinsons's disease - intracellular Lewy bodies - consists of misfolded α-synuclein. This protein can self-assemble, spread through the brain and seed its own aggregation. Aggregated α-synuclein is shown to induce mitochondrial dysfunction that leads to neuronal loss. Using human iPSC-derived SNCA triplication (3xSNCA) and isogenic control (ISO) neurons we studied whether acute exposure to fibrillar α-synuclein, or its seeding properties, induce effects on mitochondrial function and toxicity. Chronic exposure of neurons to fibrillar α-synuclein (up to 3 weeks) induces a gradual increase of endogenous α-synuclein seeding in neurons, with a decrease in the exogenous fibrillar α-synuclein in ISO and 3xSNCA neurons. Application of exogenous fibrillar α-synuclein induced mitochondrial depolarisation, impairment of complex I function, increased ROS production, oxidative stress and cell death. Notably, α-synuclein seeding following weeks of incubation almost completely restored mitochondrial function and redox balance of human neurons. Thus, mitochondrial dysfunction and oxidative stress in human neurons can be induced acutely only by transient exogenous fibrillar α-synuclein, but seeding is irrelevant to long-term mitochondrial dysfunction or toxicity. This study also indicates an acute, transient toxic insult followed by a remarkable period of adaptation and functional recovery, highlighting the resilience of human neurons.