# Elucidation of the Molecular Mechanisms of Optineurin in Glaucomatous Degeneration

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $60,188

## Abstract

ABSTRACT
Elucidating the Molecular Mechanism of Optineurin in Glaucomatous Neurodegeneration
Normal tension glaucoma (NTG) is characterized as retinal ganglion cell (RGC) degeneration in the absence of
high intraocular pressure, and currently has no sight-saving therapies. Mutations in the optineurin (OPTN) gene
have been associated with familial and sporadic NTG. OPTN acts as an adaptor to recruit ubiquitinated cargo to
autophagosomes for clearance. OPTN also has binding domains for motor proteins and is known to play a pivotal
role in cellular trafficking along the cytoskeleton. We hypothesize that a lack of cellular trafficking by
glaucoma-associated mutants of OPTN in RGCs leads to a loss-of-function of OPTN to promote NTG. No
studies have ever isolated the role of OPTN in RGCs in vivo. Using the mSncg promoter in AAV2-mediated RGC
targeting, we will overexpress OPTN-WT or OPTN-E50K in mouse RGCs. We will also use AAV2-mSncg-Cre in
floxed OPTN mice as a model of loss-of-function of OPTN. We will use in vivo retinal function assays and post-
sacrifice tissue quantification and staining to define the levels of RGC degeneration and autophagy function.
This will determine whether a gain- or loss-of-function of OPTN is associated with RGC degeneration. We have
shown that OPTN truncation in RGCs leads to RGC degeneration at 8 weeks by in vivo assays and RGC soma
and axon quantification, providing evidence for the need to study OPTN in RGCs. We have also found that after
overexpression of OPTN-WT and OPTN-E50K specifically in RGCs, only OPTN-WT is expressed in the retinal
nerve fiber layer, suggesting that OPTN-E50K can no longer function as an axon transport-related protein. RGCs
have long projection axons through the optic nerve and must have well-functioning cellular trafficking capacity to
regulate RGC health. Using immunostaining, proteomics, and axon targeting, we will determine the role of OPTN
in RGC axons and the pathology that an E50K mutation incurs. In summary, our studies will reveal the role of
OPTN in RGCs and uncover molecular mechanisms of OPTN-E50K-induced RGC degeneration.

## Key facts

- **NIH application ID:** 9982675
- **Project number:** 5F32EY029567-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Hannah Webber
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $60,188
- **Award type:** 5
- **Project period:** 2019-06-18 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982675

## Citation

> US National Institutes of Health, RePORTER application 9982675, Elucidation of the Molecular Mechanisms of Optineurin in Glaucomatous Degeneration (5F32EY029567-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982675. Licensed CC0.

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