Chaudhuri Jyotiska, Bose Neelanjan, Gong Jianke, Hall David, Rifkind Alexander, Bhaumik Dipa, Peiris T Harshani, Chamoli Manish, Le Catherine H, Liu Jianfeng, Lithgow Gordon J, Ramanathan Arvind, Xu X Z Shawn, Kapahi Pankaj
The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
The Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Department of Urology, University of California, 400 Parnassus Avenue, San Francisco, CA 94143, USA.
Curr Biol. 2016 Nov 21;26(22):3014-3025. doi: 10.1016/j.cub.2016.09.024. Epub 2016 Oct 20.
Reactive α-dicarbonyls (α-DCs), like methylglyoxal (MGO), accumulate with age and have been implicated in aging and various age-associated pathologies, such as diabetic complications and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Evolutionarily conserved glyoxalases are responsible for α-DC detoxification; however, their core biochemical regulation has remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase (glod-4/GLO1), to broadly study α-DC-related stress. We show that, in comparison to wild-type (N2, Bristol), glod-4 animals rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for α-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify α-DCs. Interestingly, this pathway is in stark contrast to the TRPA-1 activation and the ensuing calcium flux implicated in cold sensation in C. elegans, whereby DAF-16/FOXO gets activated via complementary kinase signaling. Finally, a phenotypic drug screen using C. elegans identified podocarpic acid as a novel activator of TRPA1 that rescues α-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of α-DC stress, which represents a viable option to address aging-related pathologies in diabetes and neurodegenerative diseases.
反应性α-二羰基化合物（α-DCs），如甲基乙二醛（MGO），会随着年龄的增长而积累，并与衰老以及各种与年龄相关的病理状况有关，例如糖尿病并发症和神经退行性疾病，如阿尔茨海默病和帕金森病。进化上保守的乙二醛酶负责α-DC的解毒；然而，其核心生化调节机制仍不清楚。我们基于受损的乙二醛酶（glod-4/GLO1）建立了一种秀丽隐杆线虫模型，以广泛研究与α-DC相关的应激。我们发现，与野生型（N2，布里斯托尔品系）相比，glod-4突变动物迅速表现出几种致病表型，包括感觉过敏、神经元损伤、运动能力下降和早期死亡。我们进一步证明TRPA-1/TRPA1是一种α-DCs的感受器，在蠕虫和哺乳动物之间具有保守性。此外，TRPA-1通过钙调节激酶信号激活SKN-1/Nrf，最终调节谷胱甘肽依赖性（GLO1）和辅因子非依赖性（DJ1）乙二醛酶以解毒α-DCs。有趣的是，这条途径与秀丽隐杆线虫中涉及冷觉的TRPA-1激活及随后的钙通量形成鲜明对比，在冷觉过程中DAF-16/FOXO通过互补激酶信号被激活。最后，使用秀丽隐杆线虫进行的表型药物筛选确定罗汉松酸是TRPA1的一种新型激活剂，可挽救秀丽隐杆线虫和哺乳动物细胞中α-DC诱导的病理状况。因此，我们的工作确定TRPA1是改善α-DC应激的一个真正的药物靶点，这是解决糖尿病和神经退行性疾病中与衰老相关病理状况的一个可行选择。
