为探讨叶酸添加对TAR DNA结合蛋白43（TDP-43）毒性导致的肌萎缩性侧索硬化症（amyotrophic lateral sclerosis，ALS）治疗方面产生的作用，本文选用转入人TDP-43的转基因秀丽隐杆线虫作为受试生物，探究不同浓度叶酸（0.01 mmol/L、0.025 mmol/L 、0.05 mmol/L）干预对线虫的寿命、生殖能力、瘫痪率、头部摆动频率、捕食能力与学习记忆能力的影响。结果显示，与对照组相比，0.025 mmol/L组和0.05 mmol/L组线虫寿命分别提高了22.48%和11.92%；0.025 mmol/L组线虫的生殖能力增加了25.26%；0.01 mmol/L组和0.025 mmol/L组线虫的瘫痪率分别降低了20.19%与37.62%；0.025 mmol/L组线虫头部摆动频率在叶酸干预后的第2、4、6 d分别提高了17.14%、32.88%和39.18%；三个干预组线虫的捕食能力分别提高了24.58%、60.30%和15.85%，学习记忆能力也分别提高了36.84%、57.89%和31.58%，上述结果均具有统计学差异（p<0.05）。而且，与0.01 mmol/L组和0.05 mmol/L组比较，0.025 mmol/L组线虫的瘫痪率显著下降，其他指标均显著增加，差异有统计学意义（p<0.05）。以上结果表明，叶酸添加改善了ALS线虫中hTDP-43蛋白引起的毒性效应，并且0.025 mmol/L浓度的叶酸可能是ALS线虫最佳的干预剂量。

To investigate the effect of folic acid supplementation on amyotrophic lateral sclerosis (ALS) caused by the toxicity of TAR DNA-binding protein 43 (TDP-43), the transgenic Caenorhabditis elegans (C. elegans) transformed into human TDP-43 was selected as a model organism. The lifespan, reproductive capacity, paralysis rate, head thrash frequency, feeding ability and learning and memory capacity of nematodes were evaluated after exposure to different concentrations of folic acid (0.01 mmol/L, 0.025 mmol/L, 0.05 mmol/L). The results showed that, compared with the control group, the lifespan of the nematodes in the 0.025 mmol/L group and the 0.05 mmol/L group increased by 22.48% and 11.92%, respectively. The reproductive capacity of the 0.025 mmol/L group increased by 25.26%. The paralysis rate of nematodes in 0.01 mmol/L group and 0.025 mmol/L group decreased by 20.19% and 37.62%, respectively. The frequency of head thrash in the 0.025 mmol/L group increased by 17.14%, 32.88% and 39.18% on the 2nd, 4th and 6th day after folic acid intervention, respectively. The feeding ability of the three intervention groups increased by 24.58%, 60.30% and 15.85%, respectively, and the learning and memory ability also increased by 36.84%, 57.89% and 31.58%, respectively. The above data were statistically significant (p<0.05). Compared with the 0.01 mmol/L group and the 0.05 mmol/L group, the paralysis rate of the 0.025 mmol/L group decreased significantly (p<0.05), and other indexes increased significantly (p<0.05). The results showed that folic acid supplementation could improve the toxic effects caused by hTDP-43 protein in ALS nematodes, and folic acid at the concentration of 0.025 mmol/L might be the optimal intervention dose for ALS nematodes.

国家自然科学基金项目（81373003；81874262）