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The Role of Beclin-1 Acetylation on Autophagic Flux in Alzheimer’s Disease

  • A. Raquel Esteves
  • Filipa Filipe
  • João D. Magalhães
  • Diana F. Silva
  • Sandra M. CardosoEmail author
Article

Abstract

Macroautophagy impairment plays a key role in sporadic Alzheimer’s disease (sAD) neurodegenerative process. Nevertheless, the mechanism(s) that lead to a deficiency in macroautophagy in AD remains elusive. In this work, we identify, for the first time that Beclin-1 acetylation status is implicated in the alterations in autophagy observed in AD neurodegeneration. We observed that Beclin-1 is deacetylated by sirtuin 1 (SIRT1) and acetylated by p300. In addition, Beclin-1 acetylation inhibits autophagosome maturation, leading to impairment in autophagic flux. We also analyzed some proteins known to be involved in the maturation of autophagosomes such as Rab7, which participates in the fusion step with lysosomes. We observed that increased expression of Rab7 might represent a response to boost the formation of large perinuclear lysosome clusters in accordance with an increase in lysosomal biogenesis determined by increase in LAMP-2A, LAMP-1, and cathepsin D expression in AD cells. Thus, our data provides strong evidences that Beclin-1 acetylation impairs the autophagic flux, and despite lysosomal biogenesis seems to be triggered as a compensatory response, autophagosome fusion with lysosomes is compromised contributing to AD neurodegeneration.

Keywords

Beclin-1 Autophagy Sirtuin 1 p300 Acetylation Alzheimer’s disease 

Notes

Author Contributions

FF, ARE, and DFS acquired the data; ARE and SMC discussed the results, and JDM and SMC wrote the article.

Funding Information

Work in our laboratory was supported by Fundação para a Ciência e a Tecnologia (FCT) and by EU-FEDER funding through the Operational Competitiveness Program—COMPETE grant UID/NEU/04539/2013, by the European Regional Development Fund, Centro 2020 Regional Operational Program (CENTRO-01-0145-FEDER-000012-HealthyAging2020), by Prémio Santa Casa Neurociências Mantero Belard MB-40-2016, and by Project POCI-01-0145-FEDER-030712. AR Esteves and DF Silva are supported by post-doctoral fellowship from FCT-MCTES, Portugal. JD Magalhães is supported by a MB-40-2016 fellowship.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.CNC–Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal
  2. 2.Institute of Cellular and Molecular Biology, Faculty of MedicineUniversity of CoimbraCoimbraPortugal

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