Opposing activities protect against age-onset proteotoxicity.
Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer's disease, which is associated with the misassembly of the Abeta(1-42) peptide. Aggregation-mediated Abeta(1-42) toxicity was reduced in Caenorhabditis 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.
Cohen
Ehud
E
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Bieschke
Jan
J
Perciavalle
Rhonda M
RM
Kelly
Jeffery W
JW
Dillin
Andrew
A
D000375:Aging / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D051858:Forkhead Transcription Factors; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008954:Models, Biological; D008970:Molecular Weight; D009068:Movement; D009132:Muscles / Q000378:metabolism / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; 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