Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection.
Toxic protein aggregation (proteotoxicity) is a unifying feature in the development of late-onset human neurodegenerative disorders. Reduction of insulin/IGF-1 signaling (IIS), a prominent lifespan, developmental and reproductive regulatory pathway, protects worms from proteotoxicity associated with the aggregation of the Alzheimer's disease-linked Abeta peptide. We utilized transgenic nematodes that express human Abeta and found that late life IIS reduction efficiently protects from Abeta toxicity without affecting development, reproduction or lifespan. To alleviate proteotoxic stress in the animal, the IIS requires heat shock factor (HSF)-1 to modulate a protein disaggregase, while DAF-16 regulates a presumptive active aggregase, raising the question of how these opposing activities could be co-regulated. One possibility is that HSF-1 and DAF-16 have distinct temporal requirements for protection from proteotoxicity. Using a conditional RNAi approach, we found an early requirement for HSF-1 that is distinct from the adult functions of DAF-16 for protection from proteotoxicity. Our data also indicate that late life IIS reduction can protect from proteotoxicity when it can no longer promote longevity, strengthening the prospect that IIS reduction might be a promising strategy for the treatment of neurodegenerative disorders caused by proteotoxicity.
Cohen
Ehud
E
Howard Hughes Medical Institute, Glenn Center for Aging Research, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Du
Deguo
D
Joyce
Derek
D
Kapernick
Erik A
EA
Volovik
Yuli
Y
Kelly
Jeffery W
JW
Dillin
Andrew
A
D021581:Active Transport, Cell Nucleus; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence; D051858:Forkhead Transcription Factors; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D034622:RNA Interference; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D007328:Insulin; D010446:Peptide Fragments; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); C108831:daf-16 protein, C elegans; C474710:heat shock factor-1, C elegans; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin