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bioRxiv · 10.64898/2026.01.07.698249

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

Robbins, A. B.·Ranum, P. T.·Huerto-Ocampo, I.·Kuckyr, M.·Davidson, B.
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Abstract

Huntingtons disease involves progressive corticostriatal dysfunction; however, the timing of region-specific transcriptional changes remains unresolved at cellular resolution. Here, we provide a temporal single-nucleus transcriptomic atlas of striatum and motor cortex from zQ175 knock-in mice at 6 and 18 months. This full-length Huntingtin model enables staging of progressive circuit dysfunction. Striatal projection neurons show extensive early dysregulation with progressive striosomal identity erosion, whereas cortical pyramidal neuron dysfunction was layer-specific and coincided with motor symptom onset. By modeling genotype-dependent effects, we distinguish region- and cell type-specific signatures of core disease mechanisms from age-related changes and compensatory adaptations. Integrating gene co-expression and transcription factor regulatory networks, we predict candidate regulators of stage-specific dysfunction. These findings, validated across human HD and mouse model datasets, reveal temporal dynamics of disease pathogenesis in regionally distinct and interconnected neuronal populations, establishing a framework for understanding cell type-selective vulnerability.

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Robbins, A. B., Ranum, P. T., Huerto-Ocampo, I., Kuckyr, M., Davidson, B.. 2026-01-08. Temporal single-cell atlas of full-length Huntington's disease mouse model defines stage-specific signatures of corticostriatal dysfunction. https://doi.org/10.64898/2026.01.07.698249

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