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

Huntingtons disease (HD) is an autosomal dominant 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 presence of the expansion from conception. Increasing evidence supports a neurodevelopmental component to HD; however, authentic human developing HD striatal tissue has not previously been characterised. We analysed an HD positive human fetal striatal sample alongside an age- and sex-matched control. CAG-repeat length was determined, and single-cell RNA sequencing was used to investigate gene expression. We compared the fetal HD transcriptional signature with publicly available datasets from postmortem adult HD brain tissue. We identified 2,032 differentially expressed genes and defined nine cellular clusters, each exhibiting distinct transcriptional profiles. Gene enrichment analysis revealed disruption of key biological processes across the developing HD striatum, with pathway-level dysregulation varying between clusters. There was overlap in gene expression changes between fetal and adult HD striatal tissues. 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.