Caloric restriction rescues yeast cells from alpha-synuclein toxicity through autophagic control of proteostasis

Belém Sampaio-Marques, Hélder Pereira, Ana R. Santos, Catarina Alexandra de Magalhães Teixeira, Paula Ludovico

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

α-Synuclein (SNCA) is a presynaptic protein that is associated with the pathophysiology of synucleinopathies, including Parkinson's disease. SNCA is a naturally aggregation-prone protein, which may be degraded by the ubiquitin-proteasome system (UPS) and by lysosomal degradation pathways. Besides being a target of the proteolytic systems, SNCA can also alter the function of these pathways further, contributing to the progression of neurodegeneration. Deterioration of UPS and autophagy activities with aging further aggravates this toxic cycle. Caloric restriction (CR) is still the most effective non-genetic intervention promoting lifespan extension. It is known that CR-mediated lifespan extension is linked to the regulation of proteolytic systems, but the mechanisms underlying CR rescue of SNCA toxicity remain poorly understood. This study shows that CR balances UPS and autophagy activities during aging. CR enhances UPS activity, reversing the decline of the UPS activity promoted by SNCA, and keeps autophagy at homeostatic levels. Maintenance of autophagy at homeostatic levels appears to be relevant for UPS activity and for the mechanism underlying rescue of cells from SNCA-mediated toxicity by CR.

Original languageEnglish
Pages (from-to)3821-3833
Number of pages13
JournalAging
Volume10
Issue number12
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

Keywords

  • Aging
  • Alpha-synuclein
  • Autophagy
  • Caloric restriction
  • Ubiquitin-proteasome system

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