Neuronal hyperactivity-induced oxidant stress promotes in vivo α-synuclein brain spreading

Interneuronal transfer and brain spreading of pathogenic proteins are features of neurodegenerative diseases. Pathophysiological conditions and mechanisms affecting this spreading remain poorly understood. This study investigated the relationship between neuronal activity and interneuronal transfer of alpha-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship. In a mouse model of alpha-synuclein brain spreading, hyperactivity augmented and hypoactivity attenuated protein transfer. Important features of neuronal hyperactivity reported here were an exacerbation of oxidative and nitrative reactions, pronounced accumulation of nitrated alpha-synuclein, and increased protein aggregation. Data also pointed to mitochondria as key targets and likely sources of reactive oxygen and nitrogen species within hyperactive neurons. Rescue experiments designed to counteract the increased burden of reactive oxygen species reversed hyperactivity-induced alpha-synuclein nitration, aggregation, and interneuronal transfer, providing first evidence of a causal link between these pathological effects of neuronal stimulation and indicating a mechanistic role of oxidant stress in hyperactivity-induced alpha-synuclein spreading.

Automated summary

This study revealed the influence of neuronal activity on the transfer of alpha-synuclein, with hyperactivity enhancing protein transfer and hypoactivity attenuating it. High neuronal activity exacerbated oxidative and nitrative reactions, leading to nitration of alpha-synuclein and increased protein aggregation. Mitochondria were identified as key targets and potential sources of reactive oxygen and nitrogen species within hyperactive neurons.