Structure-function dissection of huntingtin exon 1 identifies a PRD-driven modifier of neuronal toxicity in Huntington's disease

Authors

Cattaneo, E., Iennaco, R., Maffezzini, C., Maestri, S., Scolz, A., Moia, L., Cattaneo, A., Murgia, A., Trovesi, C., Cammarota, E., Cordiglieri, C., Vezzoli, E., Falqui, A., Felsenfeld, D. P., Vogt, T. F., Bachi, A., Zuccato, C.

Abstract

The Huntingtin gene (HTT) contains a conserved, yet expandable CAG repeat within exon 1. While the pathogenic expansion in Huntington's Disease (HD) is well studied, the role of surrounding domains remains unclear. Using genome-edited mini-organoids and neurons, we dissected HTT exon 1 and found species-specific toxicity: the human variant caused more severe deficits than the mouse. Swapping the proline-rich domain (PRD) - the most divergent region - revealed its key role: the mouse PRD mitigated, while the human PRD worsened neuronal phenotypes. Omics profiling showed that pathogenic human exon 1 induced broad protein dysregulation, largely reversed by mouse PRD replacement. Bioinformatics implicated the actin cytoskeleton and transcriptional coactivator MKL2/MRTFB. We validated MKL2/MRTFB dysregulation in HD models and showed that restoring its expression rescued neuronal abnormalities. These findings highlight the PRD's contribution to HD toxicity and point to MKL2/MRTFB and the cytoskeleton as candidate mediators.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 29 Jul 2026.

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