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

Xinzheng Guo, Shao-Bin Wang, Hongping Xu, Adema Ribic, Ethan J. Mohns, Yu Zhou, Xianjun Zhu, Thomas Biederer, Michael C. Crair and Bo Chen ()
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Xinzheng Guo: Yale University School of Medicine
Shao-Bin Wang: Yale University School of Medicine
Hongping Xu: Yale University School of Medicine
Adema Ribic: Tufts University School of Medicine
Ethan J. Mohns: Yale University School of Medicine
Yu Zhou: Sichuan Provincial Key Laboratory for Human Disease Gene Study and Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital
Xianjun Zhu: Sichuan Provincial Key Laboratory for Human Disease Gene Study and Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital
Thomas Biederer: Tufts University School of Medicine
Michael C. Crair: Yale University School of Medicine
Bo Chen: Yale University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms9005

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