Department of Molecular Medicine, Medical School, University of Padua, 35131, Padua, Italy.
Aptuit (Verona) S.r.l., an Evotec Company, Campus Levi-Montalcini, 37135, Verona, Italy.
Nat Commun. 2023 Jul 5;14(1):3962. doi: 10.1038/s41467-023-39552-9.
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases.
亨廷顿病（HD）是一种由亨廷顿（HTT）基因中的 CAG 重复扩展引起的神经退行性疾病。由此产生的突变 HTT（mHTT）蛋白通过多种机制诱导毒性和细胞死亡，目前尚无有效的治疗方法。在这里，我们在多能小鼠胚胎干细胞（ESCs）中进行了全基因组筛选，以鉴定 mHTT 毒性的抑制剂。在所鉴定的抑制剂中，我们关注与 HD 相关过程相关的金属反应元件结合转录因子 1（Mtf1）。Mtf1 的强制表达可抵抗 mHTT 在小鼠 ESCs 和人神经前体细胞中引起的细胞死亡和氧化应激。在斑马鱼中，Mtf1 可减少 mHTT 引起的畸形和细胞凋亡。在 R6/2 小鼠中，Mtf1 消除了运动缺陷，并减少了 mHTT 聚集体和氧化应激。我们的筛选策略能够快速在体外鉴定有前途的抑制剂基因，并在体内进行验证，它可以应用于其他单基因疾病。
