Notably, Smad3, which acts primarily downstream of the TGF-β–activin pathway and is predicted to drive early gene expression changes in HD23, was significantly upregulated in the iSPN+mut subpopulation at 8 months (Extended Data Fig. 4b), suggesting that a deficiency in TrkB signalling in iSPN+ neurons may contribute to the transcriptional dysregulation observed in the HD striatal region. Here, SMAD3 is linked to Huntington disease.