We tested genetic interactions of a mutant Htt transgene with 32 genes encoding deubiquitinases belonging to five DUB protein families and found that overexpression of Yod1, a DUB belonging to the OTU (ovarian tumor) superfamily of cysteine proteases, reduced the degeneration of photoreceptor neurons, and improved motor performance, viability and longevity of HD flies. Here, ZUP1 is linked to Huntington disease.