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Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer’s-Disease Related Pathology

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Abstract

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.

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Acknowledgments

We are grateful to Dr. Russell H Swerdlow for providing the AD patient samples. Human brain samples were obtained from the Neurological Tissue Bank, Biobanc-Hospital Clinic-IDIBAPS and from a generous gift from Professor I Ferrer Abizanda, Bellvitge Hospital Universitari, Institut Català de la Salut, Barcelona, Spain.

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Authors and Affiliations

  1. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    D. F. Silva, A. R. Esteves, C. R. Oliveira & S. M. Cardoso

  2. CNC-IBILI, University of Coimbra, Coimbra, Portugal

    D. F. Silva, A. R. Esteves, C. R. Oliveira & S. M. Cardoso

  3. Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    C. R. Oliveira

  4. Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    S. M. Cardoso

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  1. D. F. Silva
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  4. S. M. Cardoso
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Correspondence to S. M. Cardoso.

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This work was supported by funds from PEst-C/SAU/LA0001/2011-2013 to SM Cardoso. AR Esteves and DF Silva are supported by postdoctoral fellowships from the Portuguese Foundation for Science and Technology (FCT-MCTES, Portugal).

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Silva, D.F., Esteves, A.R., Oliveira, C.R. et al. Mitochondrial Metabolism Power SIRT2-Dependent Deficient Traffic Causing Alzheimer’s-Disease Related Pathology. Mol Neurobiol 54, 4021–4040 (2017). https://doi.org/10.1007/s12035-016-9951-x

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