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. HD patients with an expanded CAG HTT allele of 180 (CS97iHD180n), 109 (CS09iHD109n), or 77 CAG repeats (CS77iHD77n) and from three non-HD “controls” with 33 (CS83iCTR33n), 21 (CS00iCTR21n), or 18 (CS25iCTR18n) repeat CAG alleles. iPSCs were differentiated towards a cortical fate as described in Shi et al. (doi: 10.1038/nprot.2012.116.) for 0 (iPSC colonies), 60, 80, 100, 130 days.