title: α-Synuclein ubiquitination and novel therapeutic targets for Parkinson's disease.
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.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rott
authors.forename: Raymonde
authors.initials: R
authors.lastname: Szargel
authors.forename: Vered
authors.initials: V
authors.lastname: Shani
authors.forename: Sleman
authors.initials: S
authors.lastname: Bisharat
authors.affiliation: Department of Biochemistry, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Bat-Galim, Haifa 31096, Israel. simone@tx.technion.ac.il.
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D006801:Humans; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D051844:alpha-Synuclein