Global ubiquitome analysis of substantia nigra in doubly-mutant human alpha-synuclein transgenic mice

Progression through neuronal loss of substantia nigra pars compacta (SNpc) with Parkinson's disease depends on various protein post-translational modifications mainly comprising ubiquitination. Although many ubiquitination sites have been identified through site-specific methods, systematic quantitative proteomic analysis of pre-symptomatic Parkinson's disease remains unexplored. Using quantitative proteomics, we have globally profiled ubiquitination in SNpc tissue of a Parkinson's disease transgenic mouse model (A30P*A53 T α-synuclein, hm²α-SYN-39 mouse strain) at pre-symptomatic stage; Our datasets of 3971 ubiquitination sites in 1595 proteins provide valuable insight into pre-symptomatic Parkinson's disease. Subsequent bioinformatics analysis, including gene ontology analysis, KEGG pathway annotation, functional cluster analysis, and motif analysis were performed to annotate quantifiable targets of ubiquitination sites. Therefore, this elucidation of the dysregulation of ubiquitination has implications for understanding the pathophysiological mechanism of dopaminergic neuron degeneration and for developing novel therapeutics for Parkinson's disease.