Acetylation as a major determinant to microtubule-dependent autophagy: Relevance to Alzheimer's and Parkinson disease pathology

Publication date: Available online 17 December 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): A.R. Esteves, A.M. Palma, R. Gomes, D. Santos, D.F. Silva, S.M. CardosoAbstractProtein post-translational modifications (PTMs) that potentiate protein aggregation have been implicated in several neurological disorders, including Alzheimer's (AD) and Parkinson's disease (PD). In fact, Tau and alpha-synuclein (ASYN) undergo several PTMs potentiating their aggregation and neurotoxicity.Recent data posits a role for acetylation in Tau and ASYN aggregation. Herein we aimed to clarify the role of Sirtuin-2 (SIRT2) and HDAC6 tubulin deacetylases as well as p300 acetyltransferase in AD and PD neurodegeneration. We used transmitochondrial cybrids that recapitulate pathogenic alterations observed in sporadic PD and AD patient brains and ASYN and Tau cellular models.We confirmed that Tau protein and ASYN are microtubules (MTs)-associated proteins (MAPs). Moreover, our results suggest that α-tubulin acetylation induced by SIRT2 inhibition is functionally associated with the improvement of MT dynamic determined by decreased Tau phosphorylation and by increased Tau/tubulin and ASYN/tubulin binding. Our data provide a strong evidence for a functional role of tubulin and MAPs acetylation on autophagic vesicular traffic and cargo clearance. Additionally, we showed that an accumulation of ASYN oligomers imbalance mitochondrial dynamics, which further compromise...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research