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Originally published in Science Express on 9 February 2006
Science 10 March 2006:
Vol. 311. no. 5766, pp. 1471 - 1474
DOI: 10.1126/science.1124514
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Reports

Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases

Tali Gidalevitz,* Anat Ben-Zvi,* Kim H. Ho, Heather R. Brignull, Richard I. Morimoto{dagger}

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.

Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: r-morimoto{at}northwestern.edu

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