PDF(Pubmed)
Abstract：
Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of Caenorhabditis elegans neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study reveals that neuronal cilia defects trigger the unfolded protein response of the endoplasmic reticulum (UPRER) within intestinal cells, a process dependent on the insulin/insulin-like growth factor 1 (IGF-1) signaling transcription factor and the release of neuronal signaling molecules. While inhibiting UPRER doesn\'t alter the lifespan of wild-type worms, it normalizes the extended lifespan of ciliary mutants. Notably, deactivating the cyclic nucleotide-gated (CNG) channel TAX-4 on the ciliary membrane promotes lifespan extension through a UPRER-dependent mechanism. Conversely, constitutive activation of TAX-4 attenuates intestinal UPRER in ciliary mutants. Administering a CNG channel blocker to worm larvae activates intestinal UPRER and increases adult longevity. These findings suggest that ciliary dysfunction in sensory neurons triggers intestinal UPRER, contributing to lifespan extension and implying that transiently inhibiting ciliary channel activity may effectively prolong lifespan.
摘要：
纤毛缺陷与纤毛病有关,但是秀丽隐杆线虫神经元的感觉纤毛损伤延长了寿命，以前机制不清楚的现象。我们的研究表明，神经元纤毛缺陷会触发肠细胞内内质网（UPRER）的未折叠蛋白反应，依赖于胰岛素/胰岛素样生长因子1(IGF-1)信号转录因子和神经元信号分子释放的过程。虽然抑制UPRER不会改变野生型蠕虫的寿命，它使纤毛突变体的寿命延长正常化。值得注意的是,睫状膜上环核苷酸门控（CNG）通道TAX-4的失活通过UPRER依赖性机制促进寿命延长。相反，TAX-4的组成型激活减弱纤毛突变体中的肠UPRER。对蠕虫幼虫施用CNG通道阻断剂可激活肠道UPRER并增加成虫寿命。这些发现表明，感觉神经元的纤毛功能障碍会触发肠道UPRER，有助于延长寿命，并暗示短暂抑制睫状通道活性可以有效延长寿命。
