Optogenetic-Mediated Spatiotemporal Control of α-Synuclein Aggregation Mimics Lewy Body Formation and Triggers Neurodegeneration

Abstract

α-Synuclein (α-syn) aggregation into insoluble deposits, referred to as Lewy bodies (LBs), is the paramount pathological hallmark of Parkinson’s disease (PD) and related α-synucleinopathies. However, the mechanism by which these aggregates contribute to neurodegeneration remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of α-syn aggregation and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables real-time induction of α-syn inclusion formation with remarkable spatiotemporal resolution in living cells. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical and ultrastructural features of authentic LBs.\xa0In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission and induce dopaminergic neuronal loss and PD-like behavioral impairment. Collectively, our findings provide a controllable tool that permits for the generation, visualization and dissection of the role of protein aggregation in neurodegeneration.