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CNS & Neurological Disorders - Drug Targets
(Formerly Current Drug Targets - CNS & Neurological Disorders)
ISSN (Print): 1871-5273
ISSN (Online): 1996-3181
DOI: 10.2174/18715273113126660195      Price:  $58

α-Synuclein Ubiquitination and Novel Therapeutic Targets for Parkinson's Disease

Author(s): Ruth Rott, Raymonde Szargel, Vered Shani, Sleman Bisharat and Simone Engelender
Pages 630-637 (8)
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.
α-synuclein, autophagy, Parkinson's disease, proteasome, SIAH (Seven in Absentia Homolog), ubiquitination, USP9X.
Department of Biochemistry, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa 31096, Israel.