Recruitment of parkin to centrosome in response to proteasomal inhibition
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Parkinson's disease (PD) is a common neurodegenerative movement disorder resulting primarily from the selective loss of dopaminergic neurons in the substantia nigra pars compacta. PD is clinically characterized by a triad of resting tremor, rigidity and slowness of movement. Another major feature of typical PD is the formation of Lewy bodies. The etiology of sporadic PD is unclear. Recent studies have identified several genes that are linked to familial forms of PD, which opened a new way for us to understand the pathogenesis of sporadic PD. Among the genes identified, parkin is linked to recessively inherited PD and mutations of parkin are the most common cause of hereditary PD. Parkin is a protein-ubiquitin E3 ligase. Several substrates of parkin have been identified, but the subcellular location where parkin recognizes and ubiquitinates its substrates remains unclear. In this thesis, I examined the subcellular localization of parkin especially when proteasomes were inhibited. Here I report that parkin is recruited to the centrosome when SH-SY5Y cells or transfected HEK293 cells are treated with proteasome inhibitor lactacystin. The recruitment of parkin is dependent on concentration and duration of the treatment, and is probably mediated through its binding to γ-tubulin. The recruitment of parkin is also accompanied by the centrosomal accumulation of ubiquitinated proteins and CDCrel-1, a substrate of parkin. In addition, the centrosomal recruitment of parkin is abrogated by the microtubule-depolymerizing drug colchicine or the microtubule-stabilizing drug taxol, which indicates that an intact microtubule network is required for this effect. Taken together, my data describe a selective recruitment of parkin to the centrosome in response to proteasomal inhibition. This process may provide a subcellular locale for parkin to ubiquitinate and degrade substrate proteins critically involved in the pathogenesis of PD. In this thesis, I also describe the localization of parkin on mitotic structures such as mitotic spindles and intercellular bridges. But parkin does not seem to play an important regulatory role during cell cycle progression.