# Molecular Genetics of Age-Dependent Retinal Degeneration

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $520,880

## Abstract

Project Summary
Our long-term goal is to understand the molecular mechanisms causing human diseases associated with
aging. One possible mechanism for age-dependent diseases is acceleration of the aging process by
environmental and genetic factors. Our previous studies show that mouse models showing accelerated aging
phenotypes are powerful tools to identify such factors in the retina. An ENU-induced mutant mouse model,
FUN025, displays accelerated retinal aging, as well as certain key pathologies observed in age-related retinal
diseases including retinal pigment epithelium (RPE) cell abnormalities, inflammation and photoreceptor cell
degeneration, suggesting that the responsible gene is involved in the regulation of retinal aging, and that its
impairment leads to development of the age-dependent retinal abnormalities. In the previous funding period,
we identified that a mutation in transmembrane protein 135 (Tmem135) is responsible for the retinal
abnormalities in FUN025 mice. We found that TMEM135 localizes to mitochondria, and is involved in
mitochondrial fission. Sensitivity to oxidative stress increases in cultured Tmem135 mutant cells and mutant
retina, likely due to the mitochondrial abnormalities. Our observations indicate that the RPE is the primary site
affected by the Tmem135 mutation. In addition, we found that over-expression of wild-type Tmem135 in mice
results in RPE cell degeneration. Based on these findings, we hypothesize that proper control of mitochondrial
dynamics through TMEM135 is essential to maintain normal function and integrity of RPE cells, dysregulation
of which leads to age-dependent abnormalities. In addition to our own findings, there is increasing evidence to
show that RPE is the target of age-dependent diseases including age-related macular degeneration. However,
the etiology of RPE dysfunction/death in these age-related diseases is not well understood. In this renewal
proposal, we will investigate how defective mitochondrial dynamics due to Tmem135 result in RPE
dysfunction/degeneration. Specifically, we will 1) determine molecular pathways affected by Tmem135
mutation/over-expression in RPE cells, 2) study how mitochondrial dynamics affect the integrity and function of
the RPE and how TMEM135 is involved in this process, and 3) identify genetic modifiers of RPE cell
degeneration caused by Tmem135 overexpression. Successful completion of this project will reveal the role of
mitochondrial dynamics and Tmem135 in age-dependent changes of RPE cells, and identify factors involved in
those processes, which may lead to novel supplementation or treatment options for aging and age-related
diseases in the retina.

## Key facts

- **NIH application ID:** 10459299
- **Project number:** 5R01EY022086-08
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** AKIHIRO IKEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $520,880
- **Award type:** 5
- **Project period:** 2012-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459299

## Citation

> US National Institutes of Health, RePORTER application 10459299, Molecular Genetics of Age-Dependent Retinal Degeneration (5R01EY022086-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459299. Licensed CC0.

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