Alterations in microtubule-dependent transport, mitochondrial dysfunction, and autophagic pathology are involved in neurodegeneration observed in sporadic Parkinson's disease. However, the mechanistic link connecting these events remains elusive. We observed that NAD metabolism is altered in sporadic Parkinson's disease patient-derived cells, which contributes to Sirtuin-2 activation and subsequent decrease in acetylated-α-tubulin levels. Pharmacological inhibition of sirtuin-2 deacetylase activity selectively enhanced α-tubulin acetylation and facilitated the trafficking and clearance of misfolded proteins. Sirtuin-2 knock-out mice neurons had no alteration in microtubule assembly after exposure to MPP, allowing the maintenance of a normal autophagic flux. These data were validated using MPTP-treated sirtuin-2 knock-out mice, where no alterations in motor behavior were observed. Biochemical analysis of sporadic Parkinson's disease patient brains supports the in vitro and in vivo data. Our data provide strong evidence that sirtuin-2 controls the functional ability of the autophagic system through acetylation and highlight the association between mitochondrial metabolism and neurodegeneration in sporadic Parkinson's disease.