Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration
Jason Charish, … , Rod Bremner, Philippe P. Monnier
Jason Charish, … , Rod Bremner, Philippe P. Monnier
Published March 16, 2020
Citation Information: J Clin Invest. 2020;130(4):2054-2068. https://doi.org/10.1172/JCI125898.
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Research Article Neuroscience

Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration

Abstract

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.

Authors

Jason Charish, Alireza P. Shabanzadeh, Danian Chen, Patrick Mehlen, Santhosh Sethuramanujam, Hidekiyo Harada, Vera L. Bonilha, Gautam Awatramani, Rod Bremner, Philippe P. Monnier

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Figure 8

Improved visual function in 4Ig-treated Rd10 and RhoP23H/P23H mice.

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Improved visual function in 4Ig-treated Rd10 and RhoP23H/P23H mice. (A) ...
(A) Rd10 mice were treated with either PBS or 4Ig (1 μg/μL) on P20. Representative images of P30 retinal flat mounts of WT (C57BL/6J), 4Ig-treated Rd10, or PBS-treated Rd10 mice stained with M opsin to label cone outer segments. Images are of the dorsal retina 600 μm from optic nerve head. Scale bars: 10 μm. (B) Quantification of data from A. 4Ig treatment led to a significant increase in the length of cone outer segments compared with PBS-treated Rd10 eyes (n = 4 for each; ***P < 0.001). Significance determined by 1-way ANOVA with Tukey’s multiple-comparisons test. (C) Representative electroretinogram (ERG) traces from P30 Rd10 mice treated on P20 with either PBS or 4Ig (1 μg/μL). Traces were taken under photopic conditions at 5 cd/s/m2. (D) Quantification of b wave amplitude of 4Ig- or PBS-treated Rd10 mice under dark-adapted (scotopic) and light-adapted (photopic) conditions. Black arrow indicates beginning of flash intensities eliciting mixed rod/cone responses. 4Ig treatment significantly increased b wave amplitudes for rod-driven, mixed rod/cone-driven, and cone-driven responses (n = 7 for each; *P < 0.05). Significance determined by 2-way ANOVA with Bonferroni’s correction for multiple comparisons. (E) Left: Visual acuity was significantly improved in Rd10 mice on P28 following 4Ig injection (1 μg/μL) on P20 when compared with PBS-treated Rd10 mice. Visual acuity assessed by measuring optokinetic tracking response thresholds using the OptoMotry system (n = 10 for each; ****P < 0.0001). Significance determined by 1-way ANOVA followed by Bonferroni’s multiple-comparisons test. Right: Visual acuity was significantly improved in RhoP23H/P23H mice on P23 following 4Ig injection on P10 (n = 10; 1 μg/μL) when compared with PBS controls (n = 7; ***P < 0.001). Significance determined by Student’s t test.