Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, Emeryville, CA 94608, USA.
Proc Natl Acad Sci U S A. 2011 May 31;108(22):9274-9. doi: 10.1073/pnas.1011711108. Epub 2011 May 12.
Although many genes have been implicated in the pathogenesis of common neurodegenerative diseases, the genetic and cellular mechanisms that maintain neuronal integrity during normal aging remain elusive. Here we show that Caenorhabditis elegans touch receptor and cholinergic neurons display age-dependent morphological defects, including cytoskeletal disorganization, axon beading, and defasciculation. Progression of neuronal aging is regulated by DAF-2 and DAF-16 signaling, which also modulate adult life span. Mutations that disrupt touch-evoked sensory activity or reduce membrane excitability trigger accelerated neuronal aging, indicating that electrical activity is critical for adult neuronal integrity. Disrupting touch neuron attachment to the epithelial cells induces distinct neurodegenerative phenotypes. These results provide a detailed description of the age-dependent morphological defects that occur in identified neurons of C. elegans, demonstrate that the age of onset of these defects is regulated by specific genes, and offer experimental evidence for the importance of normal levels of neural activity in delaying neuronal aging.
尽管许多基因与常见神经退行性疾病的发病机制有关，但在正常衰老过程中维持神经元完整性的遗传和细胞机制仍不清楚。在这里，我们展示秀丽隐杆线虫的触觉感受器和胆碱能神经元会出现年龄依赖性的形态缺陷，包括细胞骨架紊乱、轴突珠化和纤维松解。神经元衰老的进展受 DAF-2 和 DAF-16 信号的调节，这也调节成年寿命。破坏触摸诱发的感觉活动或降低膜兴奋性的突变会引发加速的神经元衰老，表明电活动对成年神经元的完整性至关重要。破坏触觉神经元与上皮细胞的附着会诱导出不同的神经退行性表型。这些结果提供了秀丽隐杆线虫中鉴定神经元的年龄依赖性形态缺陷的详细描述，表明这些缺陷的发病时间受特定基因的调节，并为正常水平的神经活动在延缓神经元衰老中的重要性提供了实验证据。
