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Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases
Journal article   Open access   Peer reviewed

Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases

Tali Gidalevitz, Anat Ben-Zvi, Kim H. Ho, Heather R. Brignull and Richard I. Morimoto
Science (American Association for the Advancement of Science), v 311(5766), pp 1471-1474
10 Mar 2006
DOI: https://doi.org/10.1126/science.1124514
PMID: 16469881
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1126/science.1124514View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Numerous human diseases are associated with the chronic expression of misfolded and aggregation-prone proteins. The expansion of polyglutamine residues in unrelated proteins is associated with the early onset of neurodegenerative disease. To understand how the presence of misfolded proteins leads to cellular dysfunction, we employed Caenorhabditis elegans polyglutamine aggregation models. Here, we find that polyglutamine expansions disrupted the global balance of protein folding quality control, resulting in the loss of function of diverse metastable proteins with destabilizing temperature-sensitive mutations. In turn, these proteins, although innocuous under normal physiological conditions, enhanced the aggregation of polyglutamine proteins. Thus, weak folding mutations throughout the genome can function as modifiers of polyglutamine phenotypes and toxicity.

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524 citations in Web of Science
540 citations in Scopus

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Web of Science research areas
Biochemistry & Molecular Biology
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