widespread protein aggregation as an inherent part of aging in c. elegans广泛的蛋白质聚集在秀丽隐杆线虫衰老的一个固有部分.pdfVIP

Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans 1 2 3 1 3 Della C. David , Noah Ollikainen , Jonathan C. Trinidad , Michael P. Cary , Alma L. Burlingame , Cynthia Kenyon1* 1 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America, 2 Graduate Program in Biological and Medical Informatics, University of California San Francisco, San Francisco, California, United States of America, 3 Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America Abstract 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 b-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.