Enhanced mTORC1 signaling and protein synthesis in pathologic alpha-synuclein cellular and animal models of Parkinson’s disease

Pathologic alpha-synuclein plays an important role in the pathogenesis of alpha-synucleinopathies such as Parkinson’s disease (PD). Disruption of proteostasis is thought to be central to pathologic alpha-synuclein (alpha-syn) toxicity; however, the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic alpha-syn activates the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) leading to enhanced mRNA translation via binding tuberous sclerosis protein (TSC) 2 and destabilizing the TSC1-TSC2 complex. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescue the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the alpha-syn preformed fibril (PFF) and Drosophila alpha-syn transgenic models of pathologic alpha-syn induced degeneration. Our findings establish a potential molecular mechanism by which pathologic alpha-syn activates mTORC1 leading to enhanced protein synthesis and concomitant neurodegeneration in PD.