PROFILING OF THE DEVELOPING HUMAN AND MOUSE HUNTINGTON¿S DISEASE BRAIN AT SINGLE-CELL RESOLUTION

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. Although the mutant huntingtin protein is expressed from conception, clinical symptoms typically emerge in mid-adulthood. Imaging and molecular studies have raised the possibility that HD may include a neurodevelopmental aspect, but direct evidence at the single-cell level in the human fetal brain has been lacking. Therefore, the aim of this thesis is to investigate whether early, cell type–specific transcriptional vulnerabilities arise during neurodevelopment and whether they persist into adult pathology and might be rescued. To address this, we performed single-cell transcriptomic profiling of the lateral ganglionic eminence and cortex from a rare, anatomically intact human HD fetal brain, alongside matched controls. These data were complemented by an allelic series of HD mouse embryos and cross-compared with human post mortem brains and brain organoid models datasets. Neural progenitors emerged as the most consistently affected population in the human fetal brain, and were similarly impacted in the HD mouse model, where additional cell types were also impaired. Notably, human HD progenitor transcriptional signatures were enriched in the developing mouse LGE, possibly indicating a shared developmental vulnerability. These progenitors displayed upregulation of synaptic pathways alongside downregulation of genes involved in essential cellular machineries. Furthermore, aberrant cell-cycle re-entry was observed in neuronal populations in both species. Cross-comparison with public post-mortem HD datasets revealed that transcriptional alterations observed in fetal progenitors persist in adult tissues, potentially priming mature populations for degeneration. Importantly, cellular interactions can counteract these transcriptional defects, uncovering a fetal-to-adult rescuable signature with profound implications for HD pathogenesis and potential therapeutic intervention. Together, these data challenge the traditional view of HD as a purely late-onset neurodegenerative disorder, demonstrating instead that early transcriptional alterations affect neural progenitors persist in adulthood, and can be reversed by cellular interactions.