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 7

Improved feature detection in 4Ig-treated Rd1 eyes.

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Improved feature detection in 4Ig-treated Rd1 eyes. Rd1 mice were treate...
Rd1 mice were treated with 4Ig (1 μg/μL) on P8 and P13. Controls consisted of untreated age-matched Rd1 mice. Light-evoked activity in RGCs was recorded extracellularly using a patch electrode on P29–P35. (A) Spike rasters from 3 ON (left) and 3 OFF (right) RGCs in 4Ig-treated Rd1 retina. Shaded region indicates the duration of the stimulus (200- to 400-μm spot). Black traces below the rasters show average spike rate estimated by Gaussian convolution (σ = 50 ms). (B) Spike recordings from 2 example RGCs in control Rd1 retina illustrating the high spontaneous spike hyperactivity typically associated with photoreceptor degeneration. The bottom recording depicts the suppression of spiking at onset of light (arrow), indicating a weak residual photoreceptor response in untreated Rd1 animals. (C) A comparison of the relative population of the 3 cell types — ON and OFF, residual, and nonresponsive — in 4Ig-treated and control retina. (D) The center-surround organization of RGCs is preserved in the 4Ig-treated retina. The light response of an example ON ganglion cell to increasing spot sizes is shown. (E) The average peak responses of 10 ON and OFF RGCs to increasing spot sizes shown in D. The responses were significantly suppressed for spots larger than 400 μm (P < 0.001). (F) The response of an ON neuron to a 200-μm spot moving in 8 different directions (indicated by the arrows; velocity, 0.6 mm/s). (G) A polar plot of the responses shown in F. The responses of individual trials are shown in gray and the average in black. The direction selective index (DSI) is indicated by the solid radial line. DSI = 0.62 ± 0.07; value of 1 indicates responses to motion in only 1 direction.