Temporal single-cell atlas of full-length Huntington’s disease mouse model defines stage-specific signatures of corticostriatal dysfunction

Abstract Background Huntington’s disease (HD) involves progressive corticostriatal dysfunction, yet the temporal dynamics and cell type-specific vulnerability patterns remain incompletely understood. While recent single-cell studies in rapidly progressing models have revealed early developmental and regional changes, temporal profiling distinguishing pathogenic mechanisms from normal aging in full-length HTT models remains lacking. Resolving stage-specific temporal dynamics across interconnected striatal and cortical neuronal populations over protracted time is essential for identifying drivers of cellular dysfunction. Methods A temporal single-nucleus transcriptomic atlas was generated from striatum and motor cortex from heterozygous zQ175 knock-in mice at early symptomatic (6 months) and late symptomatic (18 months) stages. This full-length huntingtin model enables staging of progressive circuit dysfunction alongside physiological aging. The high inherited CAG repeat length of the zQ175 model places cells beyond the somatic expansion threshold associated with transcriptional dysregulation and identity erosion in vulnerable human neuronal populations, yet prior to the de-repression crisis and cell loss observed at the most extreme expansions in HD, providing a tractable window into the progressive molecular pathogenic cascade. Genotype-dependent effects were modeled to distinguish cell type-specific signatures of disease mechanisms from age-related and compensatory changes. Integration of weighted gene co-expression and transcription factor regulatory networks with protein-protein interaction databases predicted candidate regulators of stage-specific programs. Findings were validated across human HD datasets and the rapidly progressive R6/2 mouse model. Results Temporal gene and network analysis revealed diverging, converging and biphasic patterns of transcriptional changes, distinguishing progressive disease and neuronal identity loss from aging. 21 cell type-specific gene co-expression modules were validated in human HD and R6/2 mice datasets, revealing stage-specific shifts in cellular stress, proteostasis, and synaptic programs. Disease modules enriched for CAG repeat length-dependent genes resolved their temporal progression. Shared vulnerability across cortical and striatal projection neurons implicated epigenetic regulator Zswim6 and splicing factors Rbfox1 and Celf2 in corticostriatal dysfunction. Integrative network analysis identified Foxo1, Neurod2, and Npas2 as stage-specific transcriptional regulators. Cross-species validation established conserved gene regulatory modules in human HD, establishing generalizable cell type-specific gene modules of translational relevance. Conclusions This temporally resolved atlas reveals stage-specific transcriptional dynamics of disease-relevant gene expression programs and physiological trajectories in vulnerable neuronal populations. distinguished from aging alone. This work establishes an important framework for understanding the temporal and regional coordination of pathogenic mechanisms, providing molecular insights into stage-specific therapeutic intervention.