Roles of Ubiquitin Ligases and Deubiquitylases in Parkinson?s Disease

The mechanisms underlying of the specific loss of dopaminergic neurons and alpha-synuclein aggregation in the substantia nigra in Parkinson's disease (PD) is still an enigma. Abnormal protein aggregation is largely caused by dysfunction of the ubiquitin-proteasome system (UPS). Protein ubiquitination is promoted by a cascade of ubiquitinating enzymes, and is reverse-regulated by deubiquitylases (DUBs). Abnormal process in ubiquitination and deubiquitination leads to abnormal protein aggregation and inclusion body formation, which will cause the neuronal damage. Recent studies have reported that protein ubiquitination and deubiquitination play an important role in the pathogenesis of PD. E3 ubiquitin ligases, which promote protein ubiquitination, are beneficial to alpha-synuclein clearance, promote the survival of dopaminergic neurons, and maintain mitochondrial function, etc. DUBs, which remove ubiquitin of substrate proteins, inhibit alpha-synuclein degradation, regulate mitochondrial function and iron metabolic homeostasis in neurons. In this review, we summarized the mechanism of protein ubiquitination and deubiquitination involved in dopaminergic neuronal injury through E3 ubiquitin ligase and DUBs.