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Published Online August 10, 2006
Science DOI: 10.1126/science.1124646

Research Articles

Submitted on January 5, 2006
Accepted on July 24, 2006

Opposing Activities Protect Against Age Onset Proteotoxicity

Ehud Cohen 1, Jan Bieschke 2, Rhonda M. Perciavalle 1, Jeffery W. Kelly 2, Andrew Dillin 1*

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

* To whom correspondence should be addressed.
Andrew Dillin , E-mail: dillin{at}salk.edu

Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer disease (AD) which is associated with the misassembly of the A{beta}1-42 peptide. Aggregation-mediated A{beta}1-42 toxicity was reduced in C. elegans when aging was slowed by decreased insulin/insulin growth factor (IGF)-1-like signaling (IIS). The downstream transcription factors, heat shock factor-1 (HSF-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.


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