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Opposing Activities Protect Against Age-Onset Proteotoxicity
Ehud Cohen,1*
Jan Bieschke,2*
Rhonda M. Perciavalle,1
Jeffery W. Kelly,2
Andrew Dillin1
Abstract:
Aberrant protein aggregation is a common feature of late-onsetneurodegenerative diseases, including Alzheimer's disease, whichis associated with the misassembly of the Aß1-42 peptide.Aggregation-mediated Aß1-42 toxicity was reduced inCaenorhabiditis elegans when aging was slowed by decreased insulin/insulingrowth factor–1–like signaling (IIS). The downstreamtranscription factors, heat shock factor 1, and DAF-16 regulateopposing disaggregation and aggregation activities to promotecellular survival in response to constitutive toxic proteinaggregation. Because the IIS pathway is central to the regulationof longevity and youthfulness in worms, flies, and mammals,these results suggest a mechanistic link between the aging processand 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.
To whom correspondence should be addressed E-mail: dillin{at}salk.edu
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