DOI: 10.1126/science.1124514. Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases

Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases

10.1126/science.1124514

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

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.

Bibliography

Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R., & Morimoto, R. I. (2006). Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases. Science, 311(5766), 1471â1474.

Authors 5

Tali Gidalevitz (first)
Anat Ben-Zvi (additional)
Kim H. Ho (additional)
Heather R. Brignull (additional)
Richard I. Morimoto (additional)

References 33 Referenced 541

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T.G. was supported by NIH Training Grant T32 HL076139 and by an Individual NRSA F32 GM075583-01; A.B.-Z. was supported by an EMBO Long-Term Fellowship the Parkinson Foundation and the Hereditary Disease Foundation; and H.R.B. was supported by National Institute of General Medical Sciences (NIGMS) Molecular Biology of Disease Training Grant T32 GM08061. R.I.M. was supported by grants from the NIH (NIGMS National Institute of Neurological Disorders and Stroke and National Institute on Aging) the Huntington Disease Society of America Coalition for the Cure the ALS Association and the Daniel F. and Ada L. Rice Foundation. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center which is funded by the NIH National Center for Research Resources (NCRR). We thank J. West and members of the Morimoto laboratory for their discussion and comments on the manuscript and F. Moore for reagents.

Dates

Type	When
Created	19 years, 6 months ago (Feb. 9, 2006, 8:44 p.m.)
Deposited	1 year, 7 months ago (Jan. 9, 2024, 9:08 p.m.)
Indexed	3 weeks, 3 days ago (Aug. 3, 2025, 12:26 a.m.)
Issued	19 years, 5 months ago (March 10, 2006)
Published	19 years, 5 months ago (March 10, 2006)
Published Print	19 years, 5 months ago (March 10, 2006)

Funders 0

None

BibTeX

@article{Gidalevitz_2006, title={Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases}, volume={311}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1124514}, DOI={10.1126/science.1124514}, number={5766}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Gidalevitz, Tali and Ben-Zvi, Anat and Ho, Kim H. and Brignull, Heather R. and Morimoto, Richard I.}, year={2006}, month=mar, pages={1471–1474} }

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