机构：[1]Vision Division, Krembil Research Institute, Toronto, Ontario, Canada.[2]Department of Physiology,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.[3]Department of Anatomy, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.[4]Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.[5]Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy,West China Hospital, Sichuan University, Chengdu, China.四川大学华西医院[6]Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.四川大学华西医院[7]Apoptosis, Cancer and Development Laboratory, INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France.[8]Department of Biology, University of Victoria, Victoria, British Columbia, Canada.[9]Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.[10]Department of Laboratory Medicine and Pathobiology,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.[11]Department of Ophthalmology and Vision Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Inherited retinal degenerations (IRDs) are characterized by the progressive loss of photoreceptors and represent one of the most prevalent causes of blindness among working-age populations. Cyclic nucleotide dysregulation is a common pathological feature linked to numerous forms of IRD, yet the precise mechanisms through which this contributes to photoreceptor death remain elusive. Here we demonstrate that cAMP induced upregulation of the dependence receptor neogenin in the retina. Neogenin levels were also elevated in both human and murine degenerating photoreceptors. We found that overexpressing neogenin in mouse photoreceptors was sufficient to induce cell death, whereas silencing neogenin in degenerating murine photoreceptors promoted survival, thus identifying a pro-death signal in IRDs. A possible treatment strategy is modeled whereby peptide neutralization of neogenin in Rd1, Rd10, and Rho P23H-knockin mice promotes rod and cone survival and rescues visual function as measured by light-evoked retinal ganglion cell recordings, scotopic/photopic electroretinogram recordings, and visual acuity tests. These results expose neogenin as a critical link between cAMP and photoreceptor death, and identify a druggable target for the treatment of retinal degeneration.
基金：
This
work was supported by the Krembil Foundation (PPM, RB, GA),
Fighting Blindness Canada (PPM), Brain Canada (PPM, RB),
the NIH (EY027750 to VLB), a National Eye Institute P30 Core
Grant (P30EY025585 to the Cleveland Clinic Foundation), and
an unrestricted grant from Research to Prevent Blindness to the
Cleveland Clinic Foundation. JC received support from the Vision
Science Research Program of the University of Toronto. Human
donor eyes were obtained through the FFB Eye Donor Program.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Vision Division, Krembil Research Institute, Toronto, Ontario, Canada.[2]Department of Physiology,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
通讯作者：
通讯机构：[1]Vision Division, Krembil Research Institute, Toronto, Ontario, Canada.[2]Department of Physiology,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.[11]Department of Ophthalmology and Vision Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.[*1]Krembil Research Institute, 60 Leonard Avenue, Krembil Discovery Tower 8-428, Toronto, Ontario, M5T 2O8, Canada.
推荐引用方式(GB/T 7714)：
Jason Charish,Alireza P. Shabanzadeh,Danian Chen,et al.Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration.[J].The Journal of clinical investigation.2020,130(4):2054-2068.doi:10.1172/JCI125898.
APA：
Jason Charish,Alireza P. Shabanzadeh,Danian Chen,Patrick Mehlen,Santhosh Sethuramanujam...&Philippe P. Monnier.(2020).Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration..The Journal of clinical investigation,130,(4)
MLA：
Jason Charish,et al."Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration.".The Journal of clinical investigation 130..4(2020):2054-2068
医学