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Science 313 (5793): 1604-1610

Copyright © 2006 by the American Association for the Advancement of Science

Opposing Activities Protect Against Age-Onset Proteotoxicity

Ehud Cohen,1* Jan Bieschke,2* Rhonda M. Perciavalle,1 Jeffery W. Kelly,2 Andrew Dillin1{dagger}

Abstract: Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer's disease, which is associated with the misassembly of the Aß1-42 peptide. Aggregation-mediated Aß1-42 toxicity was reduced in Caenorhabiditis elegans when aging was slowed by decreased insulin/insulin growth factor–1–like signaling (IIS). The downstream transcription factors, heat shock factor 1, and DAF-16 regulate opposing disaggregation and aggregation activities to promote cellular survival in response to constitutive toxic protein aggregation. Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies, and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity.

1 Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Department of Chemistry and Skaggs Institute of Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed E-mail: dillin{at}salk.edu

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