Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons. Using a highly efficient protocol for direct reprogramming of adult human fibroblasts with chemically modified mRNA, we report the first generation of HD induced neural precursor cells (iNPs) expressing striatal lineage markers that differentiated into DARPP32+ neurons from individuals with adult-onset HD (41-57 CAG). While no transcriptional differences between normal and HD reprogrammed neurons were detected by NanoString nCounter analysis, a subpopulation of HD reprogrammed neurons contained ubiquitinated polyglutamine aggregates. Importantly, reprogrammed HD neurons exhibited impaired neuronal maturation, displaying altered neurite morphology and more depolarized resting membrane potentials. Reduced BDNF protein expression in reprogrammed HD neurons correlated with increased CAG repeat lengths and earlier symptom onset. This model represents a platform for investigating impaired neuronal maturation and screening for neuronal maturation modifiers to treat HD.

中文翻译：

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直接重编程亨廷顿病神经前体细胞产生纹状体神经元，表现出聚集和受损的神经元成熟

亨廷顿病 (HD) 是一种常染色体显性遗传的神经退行性疾病，其特征是纹状体中棘神经元进行性丧失。使用一种高效的方案，用化学修饰的 mRNA 直接重编程成人人成纤维细胞，我们报告了第一代 HD 诱导的神经前体细胞 (iNPs)，它们表达纹状体谱系标记，从成人发病的 HD (41- 57 全能神教会）。虽然通过 NanoString nCounter 分析未检测到正常和 HD 重编程神经元之间的转录差异，但 HD 重编程神经元的亚群含有泛素化的聚谷氨酰胺聚集体。重要的是，重编程的 HD 神经元表现出受损的神经元成熟，表现出改变的神经突形态和更多的去极化静息膜电位。重编程的 HD 神经元中 BDNF 蛋白表达的降低与 CAG 重复长度的增加和早期症状发作相关。该模型代表了一个研究受损神经元成熟和筛选神经元成熟修饰剂以治疗 HD 的平台。