Yeast Model of Disease Associated Mutant Ubiquitin

Washington University, Saint Louis MO

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Protein aggregation and the ubiquitin/proteasome system are important players in Alzheimer's disease (AD). Protein aggregates found in AD patients often includes proteins other than those explicit in the disease, such as a mutant ubiquitin protein (mUB). Since protein aggregation itself can impair the proteasome and, conversely, proteasomal impairment can cause protein aggregation, it is difficult to determine the cause of the disease. Cellular toxicity associated with the disease makes it challenging to separate the cause from the downstream consequence. We have developed a system, utilizing non-toxic aggregates in yeast, to determine the causal relationship of these processes. Using a tractable genetic system, we have characterized the effects of mUB associated with AD. Preliminary results suggest that mUB is a natural inhibitor of the proteasome and has a tremendous enhancing effect on protein aggregation. This unique system enables us to uncover novel factors involved in the proteasome impairment and protein aggregation. These discoveries will aid in the development of therapeutics for AD and other neurodegenerative disorders. [unreadable] [unreadable]