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

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Abstract

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.

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Abbreviations

PD:

Parkinson’s disease

SNpc:

Substantia nigra pars compacta

LBs:

Lewy Bodies

MT:

Microtubule

SNCA:

α-synuclein

SIRT2:

Sirtuin-2

HDAC6:

Histone deacetylase 6

MTOC:

Microtubule-organizing center)

MPP+ :

1-methyl-4-phenylpyridium

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

TH:

Tyrosine hydroxylase

6OHDA:

6-hydroxydopamine

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Acknowledgements

We are grateful to Dr. Russell H Swerdlow for providing the PD patients samples. Human brain samples were obtained in 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.

Author Contributions

SMC designed the experiments; ARE executed the experiments; DMA and DFS performed the autophagy-related experiments in cybrid cell lines; SDV and FCP carried out the in vivo experiments, namely, injecting MPTP to mice and determining dopamine levels; SMC, ARE, and FCP carried out the data analysis; and SMC and ARE wrote the paper.

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Authors and Affiliations

  1. CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal

    Ana R. Esteves, Daniela M. Arduíno, Diana F. Silva & Sandra M. Cardoso

  2. CNC-IBILI, Coimbra, Portugal

    Ana R. Esteves, Daniela M. Arduíno, Diana F. Silva, Sofia D. Viana, Frederico C. Pereira & Sandra M. Cardoso

  3. Pharmacy Department/Coimbra Health School, Polythecnic Institute of Coimbra, Coimbra, Portugal

    Sofia D. Viana

  4. Laboratory of Pharmacology and Experimental Therapeutics/IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Frederico C. Pereira

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

    Sandra M. Cardoso

Authors
  1. Ana R. Esteves
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  2. Daniela M. Arduíno
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  3. Diana F. Silva
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  4. Sofia D. Viana
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  5. Frederico C. Pereira
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  6. Sandra M. Cardoso
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Corresponding author

Correspondence to Sandra M. Cardoso.

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Funding

This work was supported by funds from PTDC/SAU-NEU/102710/2008, PEst-C/SAU/LA0001/2011–2013, Janssen Neuroscience Award, from Janssen Pharmaceutics to SM Cardoso. AR Esteves and DF Silva are supported by Post-Doctoral Fellowships from Portuguese Foundation for Science and Technology (FCT-MCTES, Portugal).

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The authors declare that they have no conflicts of interest.

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Esteves, A.R., Arduíno, D.M., Silva, D.F. et al. Mitochondrial Metabolism Regulates Microtubule Acetylome and Autophagy Trough Sirtuin-2: Impact for Parkinson’s Disease. Mol Neurobiol 55, 1440–1462 (2018). https://doi.org/10.1007/s12035-017-0420-y

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