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.
Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George Street, Suite 8100, New Haven, Connecticut 06511, USA.
Xinzheng
X
Guo
Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George Street, Suite 8100, New Haven, Connecticut 06511, USA.
Shao-Bin
SB
Wang
Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM B301, New Haven, Connecticut 06510, USA.
Hongping
H
Xu
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Adema
A
Ribic
Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM B301, New Haven, Connecticut 06510, USA.
Ethan J
EJ
Mohns
1] 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, Chengdu, Sichuan 610072, China [2] Hospital of University of Electronic Science and Technology of China (UESTC) &Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
Yu
Y
Zhou
1] 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, Chengdu, Sichuan 610072, China [2] Hospital of University of Electronic Science and Technology of China (UESTC) &Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
Xianjun
X
Zhu
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Thomas
T
Biederer
Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM B301, New Haven, Connecticut 06510, USA.
Michael C
MC
Crair
1] Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George Street, Suite 8100, New Haven, Connecticut 06511, USA [2] Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM B301, New Haven, Connecticut 06510, USA.
Bo
B
Chen
D000818:Animals; D004596:Electroretinography; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010786:Photoreceptor Cells / Q000187:drug effects*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D012174:Retinitis Pigmentosa / Q000188:drug therapy*; D014785:Vision, Ocular / Q000187:drug effects*
D012097:Repressor Proteins; C400300:HDAC4 protein, human; D006655:Histone Deacetylases