Ubiquitin-proteasome system and Parkinson's diseases

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by nigrostriatal dopaminergic degeneration and development of cytoplasmic inclusions known as Lewy bodies. To date, the mechanisms involved in PD pathogenesis are not clearly understood. Clues from genetic studies including identification of mutations in genes for a-synuclein, parkin, and ubiquitin carboxy hydrolase LI associated with familial PD and the presence of proteinaceous cytoplasmic inclusions in spared dopaminergic nigral neurons in sporadic cases of PD have suggested an important role for ubiquitin-proteasome system (UPS) and aberrant protein degradation. In vivo and in vitro studies have linked parkin, a-synuclein, and oxidative stress to a compromised UPS and PD pathogenesis suggesting novel therapeutic targets. (C) 2004 Elsevier Inc. All rights reserved.