# Molecular Genetics of Age-Dependent Retinal Degeneration

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $495,124

## Abstract

Dysregulation of lipid metabolism is strongly associated with age-dependent retinal
diseases including age-related macular degeneration (AMD) based on genetic and
epidemiological studies. However, the roles of dysregulated lipid metabolism in the development
and progression of age-dependent retinal diseases remain largely unknown. Mouse models
showing impairment of lipid metabolism and cellular homeostasis in the retina provide excellent
tools to study how dysregulated lipid metabolism impacts retinal health and lead to age-
dependent retinal diseases. We identified one such mouse strain harboring a mutation in
transmembrane protein 135 (Tmem135) that displays signs of accelerated aging in the retina as
well as pathologies observed in AMD including retinal pigment epithelium (RPE) cell
abnormalities, inflammation and photoreceptor cell degeneration. We found that mitochondrial
dynamics are dysregulated in Tmem135 mutant mice. In the previous funding period, we further
identified the role of TMEM135 in lipid metabolism in the retina. Our lipidomics data showed
reduced DHA levels in Tmem135 mice and indicated that TMEM135 has a role in DHA export
from peroxisomes. We also found that TMEM135 is critical for the regulation of peroxisomal
number and lipid metabolism in the retina. The number of peroxisomes is correlated with
mitochondrial morphology and function in Tmem135 mutant mice and mice overexpressing
Tmem135 (Tmgm135 TG), suggesting close interaction between these organelles. Moreover,
the Tmem135 mutation changes expression of genes associated with lipid metabolism in mouse
eyecups, which are similar to genes differentially expressed in RPE/choroid of AMD patients.
Based on these findings, we hypothesize that “Regulation of peroxisomal functions through
TMEM135 is essential to maintaining the normal function and integrity of RPE and
photoreceptor cells, dysregulation of which leads to age-dependent retinal disease phenotypes.”
In this renewal proposal, we will investigate how TMEM135 regulates lipid metabolism,
mitochondrial function and retinal function through its role in peroxisomes and DHA synthesis.
Specifically, we will 1) test the hypothesis that decreased DHA levels in Tmem135 mutant mice
are responsible for the retinal abnormalities, 2) determine the contributions of fatty acid
synthesis pathways on Tmem135 mutant retinal pathologies, and 3) test the role of peroxisomes
in mitochondrial homeostasis in the RPE. Successful completion of this project will reveal the
previously unknown role of Tmem135 in age-dependent changes of retinal 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:** 10904982
- **Project number:** 5R01EY022086-10
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** AKIHIRO IKEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $495,124
- **Award type:** 5
- **Project period:** 2012-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904982

## Citation

> US National Institutes of Health, RePORTER application 10904982, Molecular Genetics of Age-Dependent Retinal Degeneration (5R01EY022086-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10904982. Licensed CC0.

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