Human Huntington’s Disease iPSC-derived cortical neurons display altered transcriptomics, morphology and electrophysiological maturation

Huntington's disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat in the Huntingtin (HTT) gene. Induced pluripotent stem cell (iPSC) models of HD provide an opportunity to study the mechanisms underlying disease pathology in patient tissues relevant to disease. Murine studies have demonstrated that HTT is intricately involved in corticogenesis, and mutant (mt) HTT cannot compensate for the loss of non-CAG-expanded HTT. However, the critical effect of mtHTT in human corticogenesis has not yet been specifically explored and due to inherent differences in cortical development and timing between humans and mice. We therefore differentiated HD and non-diseased iPSCs into functional cortical neurons. While HD patient iPSCs can be successfully differentiated towards a cortical fate in culture, the resulting neurons display transcriptomic, morphological and functional phenotypes indicative of altered neurodevelopment. This is the first demonstration of altered corticogenesis from HD human patient cells, further supporting the potential neurodevelopmental aspect of HD.

亨廷顿舞蹈症（Huntington's disease, HD）是一类因亨廷顿蛋白（Huntingtin, HTT）基因中CAG重复序列异常扩增所引发的神经退行性疾病。亨廷顿舞蹈症的诱导多能干细胞（induced pluripotent stem cell, iPSC）模型，为研究患者相关病变组织中疾病病理的潜在机制提供了可行途径。已有小鼠研究证实，HTT深度参与皮质发生过程，且突变型（mutant, mt）HTT无法代偿非CAG扩增型HTT的缺失。然而，由于人类与小鼠在皮质发育模式及发育时序上存在固有差异，mtHTT在人类皮质发生中的关键效应尚未得到专门探究。为此，本研究将HD患者与健康个体的iPSC诱导分化为具有功能活性的皮质神经元。尽管HD患者iPSC可在体外培养中成功定向分化为皮质谱系细胞，但所得神经元呈现出转录组学、形态学及功能学层面的异常表型，提示神经发育过程发生改变。本研究首次证实HD患者来源的细胞可出现皮质发生异常，进一步支持了亨廷顿舞蹈症存在神经发育相关病理机制的可能性。