Transmembrane protein 135 regulates lipid metabolism in mouse eyecup

Abstract

Purpose : Aging is a significant factor in the development of age-related diseases but how aging disrupts cellular homeostasis to cause age-related retinal disease is unknown. We identified transmembrane protein 135 (Tmem135) as a regulator of retinal aging and its impairment results in age-related disease phenotypes. Notably, the RPE is sensitive to changes of Tmem135 function. Homozygous Tmem135 mutant (Tmem135^{FUN025/FUN025}) mice display thickened RPE, and this layer is postulated as the primary site affected by the Tmem135^FUN025 mutation. Here, we further our studies on Tmem135 in the RPE by performing RNA sequencing on posterior eyecups from Tmem135^{FUN025/FUN025} mice.

Methods : Pooled posterior eyecups from individual 2.5-month-old male and female WT, Tmem135^FUN025/+, Tmem135^{FUN025/FUN025} mice were collected for RNA sequencing. Analysis was performed using routine methods and focused on genes with more than twofold changes from wild-type (WT) controls. Genes with twofold differences were compared with two transcriptomic datasets of AMD-afflicted RPE/choroid complexes (GSE135092 and GSE29801) to determine common gene expression changes between these mouse models and AMD. Additional eyecups as well as neural retinas were collected from WT and Tmem135^{FUN025/FUN025} mice for lipid measurements and quantitation of lipid synthesis gene expression.

Results : We found significant gene expression changes in Tmem135^{FUN025/FUN025} mouse eyecups relative to WT controls. Many of the significantly-altered genes with greater than twofold differences in the Tmem135^{FUN025/FUN025} mouse eyecups were involved in lipid metabolism. We confirmed these expression changes occur in the eyecup and not in the neural retina. Consistent with these changes, we found increased cholesterol and neutral lipid accumulation in mutant Tmem135 eyecup samples. We found similar changes in genes involved in lipid metabolism between Tmem135^{FUN025/FUN025} eyecups and AMD donor eyes.

Conclusions : Our study suggests that the Tmem135 mutation affects lipid metabolism as similarly observed in human AMD eyes. Thus, Tmem135 mutant mice can serve as a good model for the role of dysregulated lipid metabolism in AMD.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.