Cohen Ehud, Bieschke Jan, Perciavalle Rhonda M, Kelly Jeffery W, Dillin Andrew
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science. 2006 Sep 15;313(5793):1604-10. doi: 10.1126/science.1124646. Epub 2006 Aug 10.
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.
异常蛋白质聚集是包括阿尔茨海默病在内的晚发性神经退行性疾病的一个共同特征，阿尔茨海默病与β淀粉样蛋白（1-42）肽的错误组装有关。当通过降低胰岛素/胰岛素样生长因子-1信号通路（IIS）减缓衰老时，秀丽隐杆线虫中聚集介导的β淀粉样蛋白（1-42）毒性降低。下游转录因子热休克因子1和DAF-16调节相反的解聚和聚集活动，以促进细胞在持续性毒性蛋白聚集反应中的存活。由于IIS通路是线虫、果蝇和哺乳动物中寿命和年轻化调节的核心，这些结果表明衰老过程与聚集介导的蛋白毒性之间存在机制联系。
