A short N-terminal domain of HDAC4 preserves photoreceptors and restores visual function in retinitis pigmentosa

Retinitis pigmentosa is a leading cause of inherited blindness, with no effective treatment currently available. Mutations primarily in genes expressed in rod photoreceptors lead to early rod death, followed by a slower phase of cone photoreceptor death. Rd1 mice provide an invaluable animal model to evaluate therapies for the disease. We previously reported that overexpression of histone deacetylase 4 (HDAC4) prolongs rod survival in rd1 mice. Here we report a key role of a short N-terminal domain of HDAC4 in photoreceptor protection. Expression of this domain suppresses multiple cell death pathways in photoreceptor degeneration, and preserves even more rd1 rods than the full-length HDAC4 protein. Expression of a short N-terminal domain of HDAC4 as a transgene in mice carrying the rd1 mutation also prolongs the survival of cone photoreceptors, and partially restores visual function. Our results may facilitate the design of a small protein therapy for some forms of retinitis pigmentosa. Retinitis pigmentosa is an inherited form of blindness caused by the progressive loss of rod and cone photoreceptors. Here, Guo et al.show that expression of a short amino-terminal domain of the histone deacetylase HDAC4 prolongs cone survival in mouse models, helping to partially restore vision.