Widespread protein aggregation as an inherent part of aging in C. elegans.
Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in beta-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease.
David
Della C
DC
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America.
Ollikainen
Noah
N
Trinidad
Jonathan C
JC
Cary
Michael P
MP
Burlingame
Alma L
AL
Kenyon
Cynthia
C
D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D040901:Proteomics
D029742:Caenorhabditis elegans Proteins; D011506:Proteins