Pathologic α-syn destabilizes the TSC 1 and 2 complex leading to mTORC1 activation, enhanced protein translation and neurodegeneration in PD.Abstract:Pathological α-synuclein (α-syn) plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson’s disease (PD). Disruption of protein homeostasis is thought be central to PD pathogenesis, however the molecular mechanism of this deregulation is poorly understood. Here we report that pathologic α-syn binds to tuberous sclerosis protein (TSC) 2 and destabilizes the TSC1-TSC2 complex leading to activation of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) and enhanced mRNA translation. Dopamine neuron loss, behavioral deficits and aberrant biochemical signaling in the α-syn preformed fibril (PFF) and Drosophila α-syn transgenic models of pathologic α-syn induced degeneration were attenuated by genetic and pharmacologic inhibition of mTOR and protein translation. Our findings establish a potential molecular mechanism by which pathologic α-syn activates mTORC1 leading to enhanced protein translation and concomitant neurodegeneration in PD.