Environmental neurotoxic chemicals-induced ubiquitin proteasome system dysfunction in the pathogenesis and progression of Parkinson's disease

Abstract

Proteolytic degradation of unwanted proteins by the ubiquitin-proteasome system (UPS) is critical for normal maintenance of various cellular functions. Parkinson's disease (PD), one of the most prevalent neurodegenerative disorders, is characterized by prominent and irreversible nigral dopaminergic neuronal loss and intracellular protein aggregations. Epidemiological studies imply both environmental neurotoxins and genetic predisposition as potential risk factors for PD, though mechanisms underlying selective dopaminergic degeneration remain unclear. Studies with experimental PD models and postmortem PD brains have provided explicit evidence for mitochondria dysfunction and oxidative stress in PD pathogenesis. Recent identification of mutants in PINK1, DJ-1, Parkin, and LRRK-2 genes compliments the oxidative stress and mitochondrial dysfunction hypotheses in dopaminergic neuronal degeneration in PD. Mutants of α-synuclein, Uch-L1 and Parkin support the involvement of UPS dysfunction in PD. Furthermore, various Parkinsonian toxicants have been shown to impair mitochondrial function, redox balances, and to some extent protein degradation machinery. Because environmental exposure to various neurotoxic agents is considered a dominant risk for development of PD, the interrelationship between neurotoxicant exposures and UPS dysfunction must be clearly understood. Elucidation of this interrelationship will help clarify 2 areas: (i) whether UPS dysfunction in PD is a primary pathogenic factor leading to nigral neuronal death or if it simply occurs as a consequence of oxidative stress and mitochondrial dysfunction and (ii) the interaction of genes and environment in the acceleration of nigral dopaminergic degeneration by targeting UPS. We review the recent evidence for UPS deficits in dopaminergic degeneration triggered by neurotoxins.