Optogenetic-Mediated Spatiotemporal Control of α-Synuclein Aggregation Disrupts Nigrostriatal Transmission and Precipitates Neurodegeneration

α-synuclein (α-syn) aggregation into insoluble deposits, referred to as Lewy bodies (LBs) is the paramount pathological hallmark of Parkinson’s disease and related α-synucleinopathies. However, how these aggregates affect neuronal homeostasis leading to neurodegeneration remains elusive. This gap in knowledge is mainly due to the lack of proper cellular and animal models to undertake such investigations. We have addressed this by developing a light-inducible protein aggregation (LIPA) system that allows for real-time induction of α-syn inclusions formation with remarkable spatial and temporal resolution in both cell culture and in vivo paradigms. We report that LIPA-induced aggregates auto-perpetuate for several days after transient light induction, and faithfully mimic several authentic features of LBs in vivo and in cell culture. Moreover, optogenetically induced α-syn aggregation in mouse midbrains compromised the nigrostriatal transmission and induced a significant dopaminergic neuronal loss and behavioural impairment. Our system provides a novel, dependable and invaluable tool by which to generate, visualize and dissect the role of protein aggregates in neurodegeneration.