Treadmill Exercise Attenuates α-Synuclein Levels by Promoting Mitochondrial Function and Autophagy Possibly via SIRT1 in the Chronic MPTP/P-Induced Mouse Model of Parkinson's Disease

Accumulation of alpha-synuclein (alpha-Syn) is significantly correlated with the presence of progressive motor deficits, which is the main symptom of Parkinson's disease (PD). Although physical exercise reduces alpha-Syn levels, the molecular mechanisms by which physical exercise decreases alpha-Syn remain unclear. We hypothesized that treadmill exercise (TE) decreases alpha-Syn levels by improving mitochondrial function and promoting autophagy via the sirtuin-1 (SIRT1) signaling pathway in the chronic 1-methyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/P)-induced mouse model of PD. We found that TE reduces alpha-Syn levels, which subsequently ameliorates dopaminergic (DAergic) neuron loss and alpha-Syn-mediated apoptotic cell death. Most importantly, TE increases SIRT1 expression, which results in increased mitochondrial biogenesis and decreased oxidative stress by activating peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). SIRT1 activation by TE also promotes autophagic clearance of alpha-Syn by inducing the activation of microtubule-associated protein 1 light chain 3 (LC3). Collectively, our results demonstrate that TE may reduce alpha-Syn levels by improving mitochondrial function and increasing autophagic flux, thereby ameliorating chronic MPTP/P-induced motor deficits in PD mice.