Mitochondrial Metabolism Regulates Microtubule Acetylome and Autophagy Trough Sirtuin-2: Impact for Parkinson’s Disease

• Published in: Molecular neurobiology Vol. 55; no. 2; pp. 1440 - 1462
• Main Authors: Esteves, Ana R., Arduíno, Daniela M., Silva, Diana F., Viana, Sofia D., Pereira, Frederico C., Cardoso, Sandra M.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-02-2018; Springer Nature B.V
• Subjects: Acetylation; Aged; Animals; Autophagy; Autophagy - physiology; Biochemical analysis; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Cell Biology; Humans; Male; Metabolism; Mice; Mice, Knockout; Microtubules - metabolism; Middle Aged; Mitochondria; Mitochondria - metabolism; MPP; MPTP; NAD; Neurobiology; Neurodegeneration; Neurology; Neurons - metabolism; Neurosciences; Parkinson Disease - metabolism; Parkinson's disease; Phagocytosis; Protein folding; Proteins; Rodents; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Tubulin; Tubulin - metabolism; Mitochondrial metabolism; Sirtuin-2; Microtubule acetylation; Macroautophagy
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0420-y

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.