Molecular function of parkin in neurodegenerative diseases

Several neurodegenerative diseases are associated with insoluble protein inclusions. Many of these inclusions contain ubiquitin, suggesting impaired degradation of the misfolded proteins by the ubiquitin-proteasome system. Understanding the mechanisms for elimination of misfolded proteins will significantly advance our understanding of neurodegenerative diseases and provide a rationale for novel therapies.; Parkin, the most commonly mutated gene in familial Parkinson's Disease, encodes an E3 ubiquitin ligase. Using expanded polyglutamine proteins and a misfolded mutant of Discosoma red fluorescent protein as model misfolded proteins, we show that parkin promotes the ubiquitination and degradation of misfolded proteins. Overexpression of parkin reduces aggregation and cytotoxicity of a polyglutamine-expanded ataxin-3 fragment. Using a cellular proteasome indicator based on a destabilized form of green fluorescent protein, we demonstrate that parkin reduces proteasome impairment and caspase-12 activation induced by expanded polyglutamine proteins. Parkin forms a complex with the expanded polyglutamine protein, heat shock protein 70 (Hsp70) and the proteasome, which may be important for the elimination of the expanded polyglutamine protein. Interestingly, Hsp70 enhances parkin binding and ubiquitination of expanded polyglutamine protein in vitro suggesting that Hsp70 may help to recruit misfolded proteins as substrates for parkin E3 ubiquitin ligase activity.; We propose that parkin may function to relieve ER stress by preserving proteasome activity in the presence of misfolded proteins. Degradation of misfolded proteins may require a specialized E3 interacting with the chaperone system. Dysfunction in these systems sensitizes cells to proteasomal impairment and ER stress and may contribute to pathogenesis of neurodegenerative diseases including Parkinson's Disease.