Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology

Mahmood Haj-Yahya, Bruno Fauvet, Yifat Herman-Bachinsky, Mirva Hejjaoui, Sudhir N. Bavikar, Subramanian Vedhanarayanan Karthikeyan, Aaron Ciechanover, Hilal A. Lashuel, Ashraf Brik

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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-Synpathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatorymechanisms involving cross-talk among different posttranslational modifications.

Original languageEnglish
Pages (from-to)17726-17731
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number44
DOIs
Publication statusPublished - 29 Oct 2013

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Haj-Yahya, M., Fauvet, B., Herman-Bachinsky, Y., Hejjaoui, M., Bavikar, S. N., Karthikeyan, S. V., Ciechanover, A., Lashuel, H. A., & Brik, A. (2013). Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology. Proceedings of the National Academy of Sciences of the United States of America, 110(44), 17726-17731. https://doi.org/10.1073/pnas.1315654110