# Synapse rescue and neuroprotection in the retina

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $387,881

## Abstract

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.

## Key facts

- **NIH application ID:** 10796947
- **Project number:** 5R01EY027411-07
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Daniel Kerschensteiner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,881
- **Award type:** 5
- **Project period:** 2017-04-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796947

## Citation

> US National Institutes of Health, RePORTER application 10796947, Synapse rescue and neuroprotection in the retina (5R01EY027411-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10796947. Licensed CC0.

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