Abstract
Accumulation of α-synuclein is key to the pathogenesis of Parkinson's disease (PD), though the exact mechanisms involved in its toxicity are still subject to debate. Increased α-synuclein expression or reduced degradation may play a role in the proteotoxicity observed in PD. Here we review the mechanisms of α-synuclein ubiquitination by different E3 ubiquitin-ligases, and its degradation via the proteasome, autophagy and lysosomes. Activators of α- synuclein ubiquitination and degradation pathways represent a plausible strategy to decrease α-synuclein burden in the disease. Nevertheless, since proteasomes and autophagy might be impaired in the disease, and because proteolytic impairment causes the accumulation of monoubiquitinated α-synuclein and the formation of toxic inclusions, compounds that promote α-synuclein monoubiquitination should be used in concert with compounds that boost these proteolytic pathways. This combined approach may therefore ease the accumulation of α-synuclein in PD and may represent a promising new avenue for the development of novel treatments for the disease.
Keywords: α-synuclein, autophagy, Parkinson's disease, proteasome, SIAH (Seven in Absentia Homolog), ubiquitination, USP9X.
CNS & Neurological Disorders - Drug Targets
Title:α-Synuclein Ubiquitination and Novel Therapeutic Targets for Parkinson's Disease
Volume: 13 Issue: 4
Author(s): Ruth Rott, Raymonde Szargel, Vered Shani, Sleman Bisharat and Simone Engelender
Affiliation:
Keywords: α-synuclein, autophagy, Parkinson's disease, proteasome, SIAH (Seven in Absentia Homolog), ubiquitination, USP9X.
Abstract: Accumulation of α-synuclein is key to the pathogenesis of Parkinson's disease (PD), though the exact mechanisms involved in its toxicity are still subject to debate. Increased α-synuclein expression or reduced degradation may play a role in the proteotoxicity observed in PD. Here we review the mechanisms of α-synuclein ubiquitination by different E3 ubiquitin-ligases, and its degradation via the proteasome, autophagy and lysosomes. Activators of α- synuclein ubiquitination and degradation pathways represent a plausible strategy to decrease α-synuclein burden in the disease. Nevertheless, since proteasomes and autophagy might be impaired in the disease, and because proteolytic impairment causes the accumulation of monoubiquitinated α-synuclein and the formation of toxic inclusions, compounds that promote α-synuclein monoubiquitination should be used in concert with compounds that boost these proteolytic pathways. This combined approach may therefore ease the accumulation of α-synuclein in PD and may represent a promising new avenue for the development of novel treatments for the disease.
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Rott Ruth, Szargel Raymonde, Shani Vered, Bisharat Sleman and Engelender Simone, α-Synuclein Ubiquitination and Novel Therapeutic Targets for Parkinson's Disease, CNS & Neurological Disorders - Drug Targets 2014; 13 (4) . https://dx.doi.org/10.2174/18715273113126660195
DOI https://dx.doi.org/10.2174/18715273113126660195 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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