Research Paper Volume 10, Issue 12 pp 3821—3833
Caloric restriction rescues yeast cells from alpha-synuclein toxicity through autophagic control of proteostasis
- 1 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- 2 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, University of Minho, Braga, Portugal
Received: May 4, 2018 Accepted: November 18, 2018 Published: December 7, 2018
https://doi.org/10.18632/aging.101675How to Cite
Copyright: Sampaio-Marques et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.