Inserm, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France.
Neurobiol Dis. 2010 Jun;38(3):425-33. doi: 10.1016/j.nbd.2010.03.002. Epub 2010 Mar 19.
Developmental pathways may be play a role in adult cell survival. However, whether they interact with longevity/cell survival pathways to confer protection against disease-associated proteotoxicity remains largely unknown. We previously reported that the inhibition of key longevity modulators such as the deacetylase sir-2.1/SIRT1 (Sir2) and its target daf-16/FoxO protects transgenics nematodes from muscle cell decline and abnormal motility produced by the expression of mutant (polyalanine-expanded) PABPN1, the oculopharyngeal muscular dystrophy (OPMD) protein. Here, we report that canonical Wnt signaling (i) modulates muscular pathology in mutant PABPN1 nematodes, and (ii) cooperates with the Sir2-FoxO longevity pathway to confer protection against mutant PABPN1 toxicity at the cellular and behavioral levels. Mutant PABPN1 toxicity was modified by genes along the canonical Wnt pathway, several of which depend on daf-16 for activity. ss-catenin and pop-1/TCF RNAi suppressed the protection from mutant PABPN1 confered by loss-of-function mutations in sir-2.1 and daf-16. Moreover, the aggravation of muscle cell pathology by increased sir-2.1 dosage was reversed by ss-catenin and pop-1 RNAi. The chemical inhibition of GSK-3ss, a repressor of ss-catenin activity, protected against mutant PABPN1 toxicity in a daf-16-dependent manner, which is consistent with a cross-talk between ss-catenin signaling and Sir2-FoxO signaling in protecting from mutant PABPN1 toxicity. Our data reveal that canonical Wnt signaling and Sir2-FoxO signaling interact to modulate diseased muscle survival, and indicate that GSK-3ss inhibitors and sirtuin inhibitors both have therapeutic potential for muscle protection in OPMD.
发育途径可能在成体细胞存活中发挥作用。然而，它们是否与长寿/细胞存活途径相互作用，以提供针对与疾病相关的蛋白毒性的保护，在很大程度上仍然未知。我们之前报道过，关键长寿调节剂的抑制，如去乙酰化酶 sir-2.1/SIRT1（Sir2）及其靶标 daf-16/FoxO，可保护转基因线虫免受由突变体（多聚丙氨酸扩展）PABPN1、眼咽型肌营养不良（OPMD）蛋白表达引起的肌肉细胞衰退和异常运动。在这里，我们报告经典 Wnt 信号（i）调节突变体 PABPN1 线虫的肌肉病理学，（ii）与 Sir2-FoxO 长寿途径合作，在细胞和行为水平上提供针对突变体 PABPN1 毒性的保护。经典 Wnt 途径中的基因改变了突变体 PABPN1 的毒性，其中几个基因的活性依赖于 daf-16。ss-catenin 和 pop-1/TCF RNAi 抑制了 sir-2.1 和 daf-16 功能丧失突变赋予的对突变体 PABPN1 毒性的保护。此外，ss-catenin 和 pop-1 RNAi 逆转了 sir-2.1 剂量增加引起的肌肉细胞病理学加重。GSK-3ss 的化学抑制，ss-catenin 活性的抑制剂，以依赖于 daf-16 的方式保护突变体 PABPN1 的毒性，这与 ss-catenin 信号和 Sir2-FoxO 信号在保护突变体 PABPN1 毒性中的相互作用一致。我们的数据表明，经典 Wnt 信号和 Sir2-FoxO 信号相互作用调节患病肌肉的存活，并表明 GSK-3ss 抑制剂和 Sirtuin 抑制剂都具有治疗 OPMD 肌肉保护的潜力。
