Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

Abstract

Summary: Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1+ neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation. : Thompson et al. describe a cyclin D1+ neural stem cell population unique to adult-onset Huntington’s disease iPSC-derived neuronal cultures, differentiated using a protocol that increases the derivation of medium spiny neurons. These findings highlight a selective CAG-length-dependent deficit in neurodevelopment. This aberrant mitotic population is ameliorated with WNT inhibition, perhaps identifying a mechanism that can be exploited for therapeutic compensation. Keywords: Huntington's disease, medium spiny neurons, WNT signaling, neural stem cells, adult-onset HD, induced pluripotent stem cells, single-cell RNA-seq, development, cell cycle