Figure 1

The ubiquitin proteasome system (UPS) and Parkinson's disease (PD). Under normal conditions, proteins destined for proteasomal degradation are tagged with a chain of ubiquitin (Ub) proteins via multiple rounds of a linear reaction catalyzed by ubiquitin activating (E1), conjugating (E2) and ligating enzymes (E3). An example of an E3 is parkin. Ubiquitylation reactions are reversed by the action of deubiquitylating enzymes (DUBs), of which UCHL1 is a member. Energy in the form of ATP is required to drive the UPS machinery. Age-related changes, exogenous stress, mitochondrial alterations and PD-linked genetic mutations in parkin, UCHL1 and α-synuclein could promote disruption of the UPS and conceivably result in the accumulation of protein aggregates or abnormal protein intermediates that could be directly detrimental to neuronal survival. Lewy bodies are thought to form as a result of an attempt by the cell to sequester these abnormal proteins. The enhancement of protein re-folding by chaperones such as Hsp70 and the clearance of protein aggregates via the stimulation of autophagy could help mitigate UPS dysfunction. Such strategies may offer innovative approaches in the treatment of PD.