THE ROLE OF NUB1 IN PATHOGENESIS OF PARKINSON'S DISEASE

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of cytosolic inclusions, called Lewy bodies (IBs). Mutations in the gene encoding alpha-synuclein, parkin, or synphilin-1 have been reported in patients with familial or sporadic Parkinson's disease. Recently, both alpha-synuclein and synphilin-1 were shown to be ubiquitinated through the E3 ubiquitin ligase activity of wild-type parkin, but not by familial-linked mutant parkin. Moreover, the coexpression of alpha-synuclein, synphilin-1, and parkin resulted in the formation of LB-like ubiquitin-positive cytosolic inclusions in cultured cells. Importantly, familial-linked mutations in parkin disrupted the formation of the ubiquitin-positive inclusions. These observations indicate that defects in the ubiquitination of LB-associated proteins are involved in the pathogenesis of Parkinson's disease. NEDD8 is a ubiquitin-like protein that covalently modifies target proteins in a manner analogous to ubiquitination. Recently, we identified a novel NEDD8-interacting protein, NUB1, that functioned like a molecular chaperone to recruit NEDD8 to the S5a subunit of the 26S proteasome for degradation. In addition to NEDD8, NUB1 interacted with synphilin-1 through its NEDDS-binding site, implying that NUB1 also recruits synphilin-1 to the S5a subunit of the 26S proteasome. Because parkin binds to the same subunit, we hypothesize that NUB1 recruits synphilin-1 to the S5a subunit for its ubiquitination by parkin. Furthermore, we hypothesize that the targeting of synphilin-1 to the S5a subunit is involved not only in the ubiquitination of synphilin-1, but also in LB formation. Indeed, we detected NUB1 in the LBs of brains from patients with Parkinson's disease, suggesting that NUB1 plays a role in LB formation or its breakdown. To test these hypotheses, we will pursue 3 Aims, which are to define 1) the role of NUB1 in the targeting of synphilin-1 to the S5a subunit, 2) the role of NUB1 in the ubiquitination of synphilin-1, and 3) the role of NUB1 in the formation of cytosolic inclusions by synphilin-1. The outcome of our research proposed here will provide a molecular basis for the involvement of NUB1 in the pathogenesis of Parkinson's disease. Furthermore, the outcome will potentially lead to the development of new diagnostic methods and therapeutic targets for Parkinson's disease.