Site-Specific Differences in Proteasome-Dependent Degradation of Monoubiquitinated α-Synuclein

•Nine monoubiquitinated α-synuclein proteins were prepared semisynthetically•Monoubiquitination toward the N terminus resulted in degradation by the proteasome•Three sites of modification did not result in α-synuclein degradation•There are site-specific differences in monoubiuqitin-mediated protein degradation

SummaryThe formation of toxic aggregates composed largely of the protein α-synuclein are a hallmark of Parkinson’s disease. Evidence from both early-onset forms of the disease in humans and animal models has shown that the progression of the disease is correlated with the expression levels of α-synuclein, suggesting that cellular mechanisms that degrade excess α-synuclein are key. We and others have shown that monoubiquitinated α-synuclein can be degraded by the 26S proteasome; however, the contributions of each of the nine known individual monoubiquitination sites were unknown. Herein, we determined the consequences of each of the modification sites using homogenous, semisynthetic proteins in combination with an in vitro proteasome turnover assay. The data suggest that the site-specific effects of monoubiquitination support different levels of α-synuclein degradation.

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