Identification of neurodevelopmental organization of the cell populations of juvenile Huntington's disease using dorso-ventral HD organoids and HD mouse embryos

Huntingtons disease (HD) is a polyglutamine neurodegenerative disease involving pathogenesis within the striatum and cerebral cortex and a neurodevelopmental component, particularly in juvenile HD form (JOHD). We established a fused HD dorsal-ventral system, imitating the cortex and striatum interaction in a single organoid to discover neurodevelopmental impairments at the level of cell populations. We found a range of early pathogenic phenotypes indicating that brain development in HD is affected by impaired neurogenesis. The phenotypes occurred already in early-stage 60-day organoids and the brain of humanized mouse embryos, at time of the beginning of the neurogenesis and choroid plexus development. We demonstrated that HD organoids and HD mouse embryonic brains had gene expression profiles of impaired maturation of neurons and increased expression of genes responsible for proliferation compared to genes responsible for differentiation in control organoids. By using scRNA-seq, the choroid plexus population was highly abundant in HD organoids and embryonic brains. Cortical and choroid plexus cell populations in HD organoids and brains co-expressed genes responsible for HTT function (mitotic spindle and cilia). The impaired maturation and the increased occurrence of the choroid plexus populations were mitigated in our compensatory model, mosaic dorsal/ventral (D/V) or V/D HD/control organoids. Finally, we found that TTR protein, a choroid plexus marker, is elevated in the adult HD mouse serum, indicating that TTR may be a promising marker for detecting HD. In summary, the fused dorso-ventral HD organoids identify a spectrum of neurodevelopmental features, including increased proliferation and delayed cell maturation. We demonstrate that the choroid plexus population is characteristic of aberrant HD neurodevelopment, and contains TTR marker, which can be translated as a blood marker in HD.