Project Summary Nervous system functions, including vision, arises from precise patterns of synaptic communication. In neurodegenerative diseases, synapse loss can long precede cell death and predict functional impairments. We recently discovered that the cell adhesion molecule (CAM) Netrin-G ligand 2 (NGL2) is required for the maintenance of rod photoreceptor synapses throughout life and that viral delivery of NGL2 can restore synapse numbers and induce the formation of extra synapses in adult wild-type and Ngl2 knockout mice, respectively. Based on these findings, we hypothesized (1) that viral delivery of NGL2 may be able to rescue synapses in inherited retinal degenerations (IRDs), a genetically heterogenous group of diseases in which photoreceptors lose synapses and die causing visual impairments, including blindness. We also hypothesized (2) that NGL2- mediated synapse rescue may be neuroprotective and slow photoreceptor death. Our preliminary data support these hypotheses, which we further test in this proposal. In Aim 1, we will examine whether synapse loss and photoreceptor degeneration progress differently IRD models on wild-type and Ngl2 KO backgrounds. We will determine to what extent and at which time viral delivery of NGL2 can rescue synapses, protect photoreceptors, and preserve vision. Finally, we will assess whether NGL2-gene therapy generalizes across IRD models that differ in pathogenesis and disease progression. CAMs nucleate large protein complexes that control synapse formation, maintenance, and function. The molecular composition and signaling mechanisms of these complexes is mostly unknown. In Aim 2, we will analyze the composition of NGL2 complexes at photoreceptor synapses and determine the contributions of NGL2’s interaction partners to synapse maintenance, rescue, and neuroprotection. Many therapeutic approaches to neurodegeneration that succeed in mice are lost in translation to humans. Differences in the anatomy, cellular composition, transcriptome, and function of neural circuits in mice vs. humans contribute to this translational challenge. We have developed an organotypic culture system of human retinas of patients undergoing enucleation surgery and organ donors. We have established an IRD model in this system. In Aim 3, we use these advances to test the ability of NGL2 and its interaction partners to rescue synapses and protect photoreceptors in the human retina. Together our studies will determine the potential of CAM-gene therapy for the treatment of neurodegenerative disease. Our mutation-agnostic approach could be widely applicable for genetically heterogenous IRDs and may be adaptable to neurodegenerative disease in other parts of the nervous system.