Figure 1.

ON-Bipolar Cells as Therapeutic Targets in Retinal Degeneration

(A) Schematic of a healthy retina on the left and a degenerated retina lacking photoreceptors on the right. PR, photoreceptor; HC, horizontal cell; OBC, ON-bipolar cell; OFFBC, OFF-bipolar cell; AC, amacrine cell; GC, ganglion cell. In retinal degeneration, the most distally remaining cells of the visual pathway are the OBCs, which can be engineered into “replacement photoreceptors” by an optogenetic gene therapy. (B) The mGluR6 signalosome in the dendritic tips of OBCs and proteins therein that are affected by loss-of-function mutations—indicated with stars—in congenital stationary night blindness. OBC-targeted gene supplementation therapies can restore function. mGluR6 is a metabotropic glutamate receptor that activates trimeric Gao/Gb3/Gy13 gating the cation channel TRPM1. LRIT3 is required for proper localization of TRPM1, and GPR179 and NYX are scaffolding proteins.