Mitochondrial Metabolism Regulates Microtubule Acetylome and Autophagy Trough Sirtuin-2: Impact for Parkinson's Disease.
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.
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal.|CNC-IBILI, Coimbra, Portugal.
Ana R
AR
Esteves
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal.|CNC-IBILI, Coimbra, Portugal.
Daniela M
DM
Arduíno
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal.|CNC-IBILI, Coimbra, Portugal.
Diana F
DF
Silva
CNC-IBILI, Coimbra, Portugal.|Pharmacy Department/Coimbra Health School, Polythecnic Institute of Coimbra, Coimbra, Portugal.
Sofia D
SD
Viana
CNC-IBILI, Coimbra, Portugal.|Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Frederico C
FC
Pereira
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal. cardoso.sandra.m@gmail.com.|CNC-IBILI, Coimbra, Portugal. cardoso.sandra.m@gmail.com.|Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal. cardoso.sandra.m@gmail.com.
Sandra M
SM
Cardoso
D000107:Acetylation; D000368:Aged; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; D056565:Sirtuin 2
Macroautophagy; Microtubule acetylation; Mitochondrial metabolism; Sirtuin-2