Cell-specific transcription dysregulation in human Huntington's disease-positive developing striatum

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the HTT gene. Progressive loss of striatal projection neurons leads to cognitive, psychiatric, and motor impairments that typically manifest in midlife, despite the expansion being present from conception. Increasing evidence supports a neurodevelopmental component to HD; however, authentic human developing HD-positive striatal tissue has not previously been characterised. We used single-cell RNA sequencing to compare an HD-positive human fetal striatal sample to an age- and sex-matched control, with CAG-repeat lengths of 16, 49 and 16, 17 respectively. We also compared the fetal HD-positive transcriptional signature with publicly available datasets from postmortem adult HD-positive brain tissue. We identified 2,032 differentially expressed genes and defined nine cellular clusters.. Gene enrichment analysis revealed alteration of key biological processes across the developing HD-positive striatum, with pathway-level dysregulation varying between clusters. There was substantial overlap in gene expression changes between fetal and adult HD-positive striatal tissues, although not in all transcriptional profiles, and some were reversed. Together, these findings demonstrate that molecular features of HD pathology are present during early human striatal development, supporting the concept that disease mechanisms are established decades prior to clinical onset.