Modulation of Tmem135 Leads to Retinal Pigmented Epithelium Pathologies in Mice.

PubMed ID: 33064130

Author(s): Landowski M, Grindel S, Shahi PK, Johnson A, Western D, Race A, Shi F, Benson J, Gao M, Santoirre E, Lee WH, Ikeda S, Pattnaik BR, Ikeda A. Modulation of Tmem135 leads to retinal pigmented epithelium pathologies in mice. Invest Ophthalmol Vis Sci. 2020 Oct 1;61(12):16. doi: 10.1167/iovs.61.12.16. PMID 33064130

Journal: Investigative Ophthalmology & Visual Science, Volume 61, Issue 12, Oct 2020

PURPOSE Aging is a critical risk factor for the development of retinal diseases, but how aging perturbs ocular homeostasis and contributes to disease is unknown. We identified transmembrane protein 135 (Tmem135) as a gene important for regulating retinal aging and mitochondrial dynamics in mice. Overexpression of Tmem135 causes mitochondrial fragmentation and pathologies in the hearts of mice. In this study, we examine the eyes of mice overexpressing wild-type Tmem135 (Tmem135 TG) and compare their phenotype to Tmem135 mutant mice.

METHODS Eyes were collected for histology, immunohistochemistry, electron microscopy, quantitative PCR, and Western blot analysis. Before tissue collection, electroretinography (ERG) was performed to assess visual function. Mouse retinal pigmented epithelium (RPE) cultures were established to visualize mitochondria.

RESULTS Pathologies were observed only in the RPE of Tmem135 TG mice, including degeneration, migratory cells, vacuolization, dysmorphogenesis, cell enlargement, and basal laminar deposit formation despite similar augmented levels of Tmem135 in the eyecup (RPE/choroid/sclera) and neural retina. We observed reduced mitochondria number and size in the Tmem135 TG RPE. ERG amplitudes were decreased in 365-day-old mice overexpressing Tmem135 that correlated with reduced expression of RPE cell markers. In Tmem135 mutant mice, RPE cells are thicker, smaller, and denser than their littermate controls without any signs of degeneration.

CONCLUSIONS Overexpression and mutation of Tmem135 cause contrasting RPE abnormalities in mice that correlate with changes in mitochondrial shape and size (overfragmented in TG vs. overfused in mutant). We conclude proper regulation of mitochondrial homeostasis by TMEM135 is critical for RPE health.