The up-regulation of Ryk prior to pathology in 128Q nematodes, the up-regulation of Ryk at the mRNA and protein levels in mutant htt striatal cells derived from HdhQ111 mice, and the converging evidence for nuclear Ryk-ICD to mediate Ryk neurotoxicity by altering FOXO activity suggest that the inhibition of the Ryk-ICD pathway may have therapeutic potential in HD. Here, HTT is linked to Huntington disease.