Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, 116021, China.
Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging (NIA), National Institutes of Health, Bethesda, MD, United States.
Free Radic Biol Med. 2022 Mar;181:52-61. doi: 10.1016/j.freeradbiomed.2022.01.030. Epub 2022 Feb 1.
Mutations in Cu/Zn-superoxide dismutase 1 (SOD1) are linked to amyotrophic lateral sclerosis (ALS). Using a line of ALS-related mutant human SOD1 (hSOD1) transgenic Caenorhabditis elegans, we determined the effects of metformin on the progression of ALS-like pathological abnormalities. We found that metformin significantly extended the lifespan, improved motor performance, and enhanced antioxidant activity of mutant worms. We further showed that metformin enhanced expression of lgg-1, daf-16, skn-1 and other genes known to regulate autophagy, longevity and oxidative stress in hSOD1 transgenic worms. Accordingly, overexpression of lgg-1 or daf-16 attenuated the aging and pathological abnormalities of mutant human SOD1 worms, while genetic deletion of lgg-1 or daf-16 abolished the beneficial effects of metformin. Collectively, we demonstrate that metformin protects against mutant SOD1-induced cytotoxicity in part through enhancement of autophagy and extends lifespan through daf-16 pathway. Our findings suggest that metformin could be further explored as a potential therapeutic agent in treating ALS.
铜/锌超氧化物歧化酶 1（SOD1）中的突变与肌萎缩侧索硬化症（ALS）有关。利用一系列与 ALS 相关的突变型人 SOD1（hSOD1）转基因秀丽隐杆线虫，我们确定了二甲双胍对 ALS 样病理异常进展的影响。我们发现二甲双胍能显著延长寿命、改善运动性能并增强突变型线虫的抗氧化活性。我们进一步表明，二甲双胍增强了已知调节自噬、长寿和氧化应激的 lgg-1、daf-16、skn-1 等基因在 hSOD1 转基因线虫中的表达。因此，lgg-1 或 daf-16 的过表达减轻了突变型人 SOD1 线虫的衰老和病理异常，而 lgg-1 或 daf-16 的遗传缺失则消除了二甲双胍的有益作用。总之，我们证明二甲双胍通过增强自噬来保护突变型 SOD1 诱导的细胞毒性，并通过 daf-16 通路延长寿命。我们的研究结果表明，二甲双胍可能作为治疗 ALS 的潜在治疗剂进一步探索。
