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• W1978677170 endingPage "e1000382" @default.
• W1978677170 startingPage "e1000382" @default.
• W1978677170 abstract "Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of AD, much less is known about the sporadic cases. Aggregates found in both familial and sporadic AD often include proteins other than those typically associated with the disease. One such protein is a mutant form of ubiquitin, UBB+1, a frameshift product generated by molecular misreading of a wild-type ubiquitin gene. UBB+1 has been associated with multiple disorders. UBB+1 cannot function as a ubiquitin molecule, and it is itself a substrate for degradation by the ubiquitin/proteasome system (UPS). Accumulation of UBB+1 impairs the proteasome system and enhances toxic protein aggregation, ultimately resulting in cell death. Here, we describe a novel model system to investigate how UBB+1 impairs UPS function and whether it plays a causal role in protein aggregation. We expressed a protein analogous to UBB+1 in yeast (Ubext) and demonstrated that it caused UPS impairment. Blocking ubiquitination of Ubext or weakening its interactions with other ubiquitin-processing proteins reduced the UPS impairment. Expression of Ubext altered the conjugation of wild-type ubiquitin to a UPS substrate. The expression of Ubext markedly enhanced cellular susceptibility to toxic protein aggregates but, surprisingly, did not induce or alter nontoxic protein aggregates in yeast. Taken together, these results suggest that Ubext interacts with more than one protein to elicit impairment of the UPS and affect protein aggregate toxicity. Furthermore, we suggest a model whereby chronic UPS impairment could inflict deleterious consequences on proper protein aggregate sequestration." @default.
• W1978677170 created "2016-06-24" @default.
• W1978677170 creator A5008856745 @default.
• W1978677170 creator A5081342912 @default.
• W1978677170 date "2009-02-13" @default.
• W1978677170 modified "2023-10-01" @default.
• W1978677170 title "Disease-Associated Mutant Ubiquitin Causes Proteasomal Impairment and Enhances the Toxicity of Protein Aggregates" @default.
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• W1978677170 doi "https://doi.org/10.1371/journal.pgen.1000382" @default.
• W1978677170 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2633047" @default.
• W1978677170 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19214209" @default.
• W1978677170 hasPublicationYear "2009" @default.
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