# A novel neuroprotective role of optic atrophy 1 protein

> **NIH NIH R21** · AUGUSTA UNIVERSITY · 2021 · $224,070

## Abstract

Project summary
Degeneration of retinal ganglion cells (RGCs) is the major cause for blindness in optic neuropathies and
glaucoma. The degenerated RGCs cannot be repaired, and currently, there are no treatments that regenerate
RGCs. Stem cell-derived RGC replacement is likely the only treatment option; however, functional restoration of
retina remains challenging and difficult. Neuroprotection is a more practical approach that prevents RGC
degeneration and prolongs RGC survival, which can delay vision loss. Retina and optic nerve represent highly
energy-demanding systems, requiring proper mitochondrial function. One of the mechanisms of RGC death is
excitotoxicity that induces mitochondrial permeability transition (MPT), leading to mitochondrial dysfunction and
RGC degeneration. The protein optic atrophy 1 (OPA1) plays a critical role in maintaining mitochondrial function,
as mutations in OPA1 gene causes hereditary autosomal dominant optic atrophy. OPA1 is known to have a dual
function, mediating fusion of mitochondrial inner membrane (IM) and maintaining cristae structure. In
mitochondria, OPA1 exists as IM-anchored long L-OPA1 and short soluble S-OPA1 that is generated by a
cleavage of L-OPA1. Although S-OPA1 had been considered a functionally insignificant cleavage product, our
recent study demonstrated that S-OPA1 is competent for maintaining mitochondrial function. Importantly, our
ongoing studies obtained new evidence that S-OPA1 renders improved cell survival under stress conditions by
decreasing MPT. Therefore, in this proposal, we will define the new OPA1 mechanism for regulating MPT and
explore its potential application for RGC neuroprotective therapy. Our central hypothesis is that S-OPA1 supports
RGC survival under excitotoxic stress by decreasing MPT. We propose two specific aims to test our hypothesis.
In Aim 1, we will determine the molecular mechanisms by which L- and S-OPA1 regulate MPT sensitivity. Using
L- and S-OPA1-specific cells, we will alter OPA1 cleavage and oligomerization, and evaluate how they change
MPT sensitivity and cell death. In aim 2, we will determine whether increasing the S-OPA1 level improves RGC
survival under stress. Using virus-mediated gene transfer, we will test the effects of changing the levels of L- and
S-OPA1 on RGC survival under excitotoxic stress in vitro and in vivo. This proposal is designed to define a new,
third role of OPA1, as an MPT regulator, and to test its therapeutic potential for neuroprotective therapy. New
information from the proposed studies will add a novel paradigm to the current understanding of OPA1 function
and MPT regulation, and help developing a new strategy for ameliorating RGC degeneration.

## Key facts

- **NIH application ID:** 10246780
- **Project number:** 5R21EY031483-02
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** YISANG YOON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $224,070
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246780

## Citation

> US National Institutes of Health, RePORTER application 10246780, A novel neuroprotective role of optic atrophy 1 protein (5R21EY031483-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246780. Licensed CC0.

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