A48 Expanded HTT cag repeats disrupt the balance between neural progenitor expansion and differentiation in isogenic human cerebral organoids. (September 2018)

• Record Type: Journal Article
• Authors: Zhang, Jinqiu; Ooi, Jolene; Langley, Sarah R; Aning, Obed Akwasi; Renner, Magdalena; Cheok, Chit Fang; Petretto, Enrico; Knoblich, Juergen A; Pouladi, Mahmoud A
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 89(2018)Supplement 1
• Page Start: A17
• Page End: A17
• Publication Date: 2018-09
• Subjects: human pluripotent stem cells -- organoids -- neurodevelopment -- CAG repeat length -- juvenile HD; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2018-EHDN.46
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Huntington disease (HD) manifests in both adult and juvenile forms. A widely accepted view posits that mutant HTT gene carriers undergo normal brain development followed some years later by a degenerative phase that ultimately results in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD raise the possibility of abnormal neurodevelopment. Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Furthermore, the impact of CAG repeat length on neurodevelopment has not been addressed to date. Using a panel of isogenic HD hESCs and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in a HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids. We confirmed this finding using HD patient-derived hiPSCs. Mechanistically, we show using chimerism experiments that this phenomenon is driven largely by cell intrinsic processes. Transcriptional profiling of cerebral organoids and time-lapse imaging of neural stem cells further reveal impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors which collectively contribute to premature neuronal differentiation. Overall, our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our study further supports the notion that HD may not be a purely neurodegenerative disorder and that abnormal neurodevelopment may be a component of HD pathophysiology.