THESIS
2019
xvi, 118 pages : illustrations (chiefly color) ; 30 cm
Abstract
Spinocerebellar Ataxia type 3 (SCA3) is an autosomal dominant polyglutamine disease
characterized by progressive neurodegeneration that leads to impaired motor coordination and
other symptoms. Exact disease mechanism of SCA3 is not fully understood and there is currently no known therapy to prevent disease progression. SCA3 is solely caused by CAG expansion of the gene ATXN3, which encodes a deubiquitinase with a unique deubiquitinating mechanism. In a yeast-two hybrid screening, ATXN3 was found to interact with PICK1, an adaptor protein with important functions in protein trafficking inside the central nervous system and other organs. In addition, PICK1 was found to regulate the cell loss caused by SCA3
through an unknown pathway in a Drosophila model. However, none of these studies...[
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Spinocerebellar Ataxia type 3 (SCA3) is an autosomal dominant polyglutamine disease
characterized by progressive neurodegeneration that leads to impaired motor coordination and
other symptoms. Exact disease mechanism of SCA3 is not fully understood and there is currently no known therapy to prevent disease progression. SCA3 is solely caused by CAG expansion of the gene ATXN3, which encodes a deubiquitinase with a unique deubiquitinating mechanism. In a yeast-two hybrid screening, ATXN3 was found to interact with PICK1, an adaptor protein with important functions in protein trafficking inside the central nervous system and other organs. In addition, PICK1 was found to regulate the cell loss caused by SCA3
through an unknown pathway in a Drosophila model. However, none of these studies were done on mammalian systems and the mechanism is not clear.
In this study, PICK1 localization was found to be sensitive towards stress. Photo-stress could induce PICK1 localization change to clusters, while heat stress, proteasome stress and arsenite stress could all induce PICK1 to localize to the perinuclear structure. In which, sodium arsenite induced PICK1 localization change very potently. The perinuclear structure formed by PICK1 was inhibited when microtubule transport activities was halted by nocodazole or by expression of dynactin dominant negative mutant p150glued-CC1. The structure is also caged by intermediate filament vimentin, strongly suggesting that it is a canonical aggresome. PICK1 was characterized to bind and form co-cluster with the AMPA receptor GluR2 via its PDZ domain. Under arsenite stress, PICK1 was redirected to form aggresome while the co-clusters quickly dispersed.
PICK1 was ubiquitously expressed but with its function only characterized in secretory cells. These results suggest that PICK1 has a stress response function in general cell lines. The
wide range of stress able to induce PICK1 to localize to aggresome indicates a converging
signalling pathway awaiting to be discovered.
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