title: Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology.
abstract: Ubiquitination regulates, via different modes of modifications, a variety of biological processes, and aberrations in the process have been implicated in the pathogenesis of several neurodegenerative diseases. However, our ability to dissect the pathophysiological relevance of the ubiquitination code has been hampered due to the lack of methods that allow site-specific introduction of ubiquitin (Ub) chains to a specific substrate. Here, we describe chemical and semisynthetic strategies for site-specific incorporation of K48-linked di- or tetra-Ub chains onto the side chain of Lys12 of α-Synuclein (α-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating α-Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common α-Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications.
authors.affiliation: Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Haj-Yahya
authors.forename: Bruno
authors.initials: B
authors.lastname: Fauvet
authors.forename: Yifat
authors.initials: Y
authors.lastname: Herman-Bachinsky
authors.forename: Mirva
authors.initials: M
authors.lastname: Hejjaoui
authors.forename: Sudhir N
authors.initials: SN
authors.lastname: Bavikar
authors.forename: Subramanian Vedhanarayanan
authors.initials: SV
authors.lastname: Karthikeyan
authors.forename: Aaron
authors.initials: A
authors.lastname: Ciechanover
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.forename: Ashraf
authors.initials: A
authors.lastname: Brik
mesh_terms: D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism / Q000503:physiopathology*; D010766:Phosphorylation; D025821:Polyubiquitin / Q000138:chemical synthesis / Q000737:chemistry*; D015202:Protein Engineering / Q000379:methods*; D055550:Protein Stability; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D051844:alpha-Synuclein; D025821:Polyubiquitin
keywords: amyloid; chemical protein synthesis; fibrils; post-translational modifications; proteasome
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