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.