We proposed that endogenous DREAM silencing in HD may be part of an early endogenous neuroprotective mechanism since (i) induced DREAM haplodeficiency in R6/2 mice, a transgenic HD mouse model, delayed the onset of motor dysfunction, reduced striatal atrophy, and prolonged lifespan, (ii) DREAM overexpression has the opposite effect in R6/2 mice and sensitized HD knock-in cells to mitochondrial stress, and (iii) blocking DREAM activity with DREAM-interacting molecules like repaglinide (RP) or PC330 reduced disease symptoms and cell viability. This evidence concerns the gene KCNIP3 and Huntington disease.