Semisynthetic, Site-Specific Ubiquitin Modification of α-Synuclein Reveals Differential Effects on Aggregation

The process of neurodegeneration in Parkinson's Disease is intimately associated with the aggregation of the protein a-synuclein into toxic oligomers and fibrils. Interestingly, many of these protein aggregates are found to be post-translationally modified by ubiquitin at several different lysine residues. However, the inability to generate homogeneously ubiquitin modified a-synuclein at each site has prevented the understanding of the specific biochemical consequences. We have used protein semisynthesis to generate nine site-specifically ubiquitin modified alpha-synuclein derivatives and have demonstrated that different ubiquitination sites have differential effects on alpha-synuclein aggregation.