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Elucidating the mechanism of action of a small molecule proteostasis regulator with potential relevance for treatment of the lysosomal storage disease, mucopolysaccharidosis I

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Thesis type
(Thesis) M.Sc.
Date created
The lysosomal storage disease Mucopolysaccharidosis I, involving lysosomal deficiency of α-L-iduronidase (IDUA), is often characterized by extensive ER-associated degradation (ERAD) of missense mutant IDUAs, folding variants which often retain residual activity. Compound X-372, identified from a plant cell-based screen of 1,040 FDA-approved drugs, enhanced the post-ER transport of ERAD-prone P533R-IDUA. Here, dose response studies of compound treatment on Nicotiana tabacum BY2 protoplasts, expressing human wild-type and ERAD-prone R383H-IDUA, not only validated the rescuing effect of X-372, but also indicated this effect occurred via augmenting a general cellular process. Microarray analysis and subsequent quantitative PCR validation of candidate genes showed that the therapeutic effect of X-372 was linked to augmented sulfur assimilation. Reduced glutathione - a product of the sulfur assimilation pathway that is also a potent cellular antioxidant – is a target for future studies to identify the specific means by which X-372 enhances the post-ER transport of ERAD-prone folding mutants.
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This thesis may be printed or downloaded for non-commercial research and scholarly purposes.
Scholarly level
Supervisor or Senior Supervisor
Thesis advisor: Kermode, Allison
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