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Biomolecules 2015, 5(2), 735-757; doi:10.3390/biom5020735

Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

1
Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga 4710-057, Portugal
2
ICVS/3B's—PT Government Associate Laboratory, Braga/Guimarães 4710-057, Portugal
*
Author to whom correspondence should be addressed.
Academic Editor: Stephan N. Witt
Received: 12 March 2015 / Revised: 13 April 2015 / Accepted: 27 April 2015 / Published: 4 May 2015
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Abstract

Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. α-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for α-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins’s role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from α-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of α-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies. View Full-Text
Keywords: α-synuclein; ubiquitin-proteasome system; chaperone-mediated autophagy; (macro)autophagy; aging; mitochondria; sirtuins α-synuclein; ubiquitin-proteasome system; chaperone-mediated autophagy; (macro)autophagy; aging; mitochondria; sirtuins
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Sampaio-Marques, B.; Ludovico, P. Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies. Biomolecules 2015, 5, 735-757.

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