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

作者：Rott Ruth; Szargel Raymonde; Shani Vered; Bisharat Sleman; Engelender Simone^*

来源：CNS & Neurological Disorders-Drug Targets, 2014, 13(4): 630-637.

• alpha-synuclein
• autophagy
• Parkinson's disease
• proteasome
• SIAH (Seven in Absentia Homolog)
• ubiquitination
• USP9X

Accumulation of alpha-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 alpha-synuclein expression or reduced degradation may play a role in the proteotoxicity observed in PD. Here we review the mechanisms of alpha-synuclein ubiquitination by different E3 ubiquitin-ligases, and its degradation via the proteasome, autophagy and lysosomes. Activators of alpha-synuclein ubiquitination and degradation pathways represent a plausible strategy to decrease alpha-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 alpha-synuclein and the formation of toxic inclusions, compounds that promote alpha-synuclein monoubiquitination should be used in concert with compounds that boost these proteolytic pathways. This combined approach may therefore ease the accumulation of alpha-synuclein in PD and may represent a promising new avenue for the development of novel treatments for the disease.

• 出版日期2014