Vision Division, Krembil Research Institute, Toronto, Ontario, Canada.
Department of Physiology and.
J Clin Invest. 2020 Apr 1;130(4):2054-2068. doi: 10.1172/JCI125898.
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.
遗传性视网膜变性（IRDs）的特征是感光细胞的进行性丧失，是工作年龄段人群失明的最常见原因之一。环核苷酸调节异常是与多种 IRD 相关的共同病理特征，但导致感光细胞死亡的确切机制仍不清楚。在这里，我们证明 cAMP 可诱导视网膜中依赖受体 neogenin 的上调。neogenin 水平在人类和鼠退化的感光细胞中也升高。我们发现，在小鼠感光细胞中过表达 neogenin 足以诱导细胞死亡，而在退化的小鼠感光细胞中沉默 neogenin 则促进存活，从而确定了 IRD 中的促死亡信号。可以模拟一种可能的治疗策略，即用肽中和 Rd1、Rd10 和 Rho P23H 敲入小鼠中的 neogenin，以促进视杆和视锥细胞的存活，并通过光诱发的视网膜神经节细胞记录、暗/明视电图记录和视力测试来挽救视觉功能。这些结果表明 neogenin 是 cAMP 和感光细胞死亡之间的关键联系，并确定了治疗视网膜变性的可用药靶标。
