Lewy bodies are the pathological hallmark of Parkinson's disease (PD), and they are primarily composed of alpha-synuclein, a 140-AA protein that has a propensity to aggregate. Lewy bodies also contain ubiquitin. Disorders of the ubiquitin-proteasomeal degradation pathway are implicated in a number of neurodegenerative diseases, such as Alzheimer's disease. This suggests that this pathway could also be important in the pathophysiology of PD. Our preliminary evidence suggests that aggregated alpha synuclein might also inhibit the proteasomal-degradation pathway, both ubiquitin-independent and ubiquitin-dependent, which links mechanisms of neurodegeneration associated with alpha synuclein with mechanisms found in other neurodegenerative diseases. This proposal will address the hypothesis that aggregates of alpha synuclein bind to and obstruct the proteasome, preventing protein degradation. This could be associated with the cell death in PD. The hypothesis will be investigated in two aims. In the first aim, we will determine whether human alpha synuclein interacts with components of the proteasome in human brain. In addition to confirming evidence seen with rat alpha synuclein and Tat binding protein 1 (TBP1), we will investigate co-localization of synuclein and the proteasome; and we will identify other proteasomal components that alpha synuclein may associate. In the second aim, we will determine whether monomeric and aggregated alpha synuclein inhibit the 20S ubiquitin-independent, 26S ubiquitin-independent, and 26S ubiquitin-dependent proteasomes, both in vitro and in vivo. The research in this proposal will provide insight into the mechanism of neurodegeneration in PD and suggest novel targets for therapeutic intervention. ? ?
