α-Synuclein Ubiquitination and Novel Therapeutic Targets for Parkinson's Disease
Ruth Rott, Raymonde Szargel, Vered Shani, Sleman Bisharat and Simone Engelender
Affiliation: Department of Biochemistry, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa 31096, Israel.
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,
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