Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer’s-Disease Related Pathology
| العنوان: | Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer’s-Disease Related Pathology |
|---|---|
| المؤلفون: | Sandra M. Cardoso, A. R. Esteves, Diana Silva, Catarina R. Oliveira |
| المصدر: | Europe PubMed Central |
| بيانات النشر: | Springer Science and Business Media LLC, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Neuroscience (miscellaneous), Mitochondrion, SIRT2, Microtubules, Mitochondrial Dynamics, Models, Biological, 03 medical and health sciences, Cellular and Molecular Neuroscience, Sirtuin 2, 0302 clinical medicine, Alzheimer Disease, Tubulin, Microtubule, Mitophagy, Autophagy, medicine, Animals, Humans, Cognitive Dysfunction, Aged, Aged, 80 and over, Membrane Potential, Mitochondrial, Mice, Knockout, biology, Neurodegeneration, Brain, Reproducibility of Results, Acetylation, Cell Differentiation, Middle Aged, medicine.disease, Mitochondria, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, Neurology, biology.protein, Female, Lysosomes, 030217 neurology & neurosurgery |
| الوصف: | Multiple lines of evidence state a major role for mitochondrial dysfunction in sporadic Alzheimer's disease (AD) etiopathogenesis. However, the molecular mechanism(s) triggered by mitochondrial deficits that lead to neurodegeneration remain elusive. Herein, we propose a new mechanism by which mitochondrial loss of potential leads to a dysfunction in autophagy/mitophagy due to the overactivation of SIRT2, a tubulin deacetylase that regulates microtubule network acetylation, and provide insights into the association between metabolism, phosphorylation, and Aβ aggregation. We observed an increase in SIRT2 levels and a decrease in the acetylation of lys40 of tubulin in AD cells containing patient mtDNA as well as in AD brains. SIRT2 loss of function either with AK1 (a specific SIRT2 inhibitor) or by SIRT2 knockout recovers microtubule stabilization and improves autophagy, favoring cell survival through the elimination of toxic Aβ oligomers. Our data provide strong evidence for a functional role of tubulin acetylation on autophagic vesicle traffic and mitochondria degradation. We propose that SIRT2 inhibition may improve microtubule assembly thus representing a valid approach as disease-modifying therapy for AD. |
| تدمد: | 1559-1182 0893-7648 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c0370cdbe251431dd34f4310fb9a91a6Test https://doi.org/10.1007/s12035-016-9951-xTest |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....c0370cdbe251431dd34f4310fb9a91a6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15591182 08937648 |
|---|