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Samuel Grindel, Michael Landowski, Adrienne Race, Abigail Johnson, Daniel Western, Marvin Gao, Jonathan Benson, Evelyn Santoirre, Pawan Shahi, Wei-Hua Lee, Bikash R Pattnaik, Sakae Ikeda, Akihiro Ikeda; Overexpression of TMEM135 Causes Progressive RPE Atrophy Dependent on Mouse Genetic Background. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3536.
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© ARVO (1962-2015); The Authors (2016-present)
Transmembrane protein 135 (TMEM135) is a critical protein that prevents accelerated aging retinal pathologies and regulates mitochondrial dynamics in mice. Overexpression of wildtype TMEM135 increases mitochondrial fragmentation and leads to early onset age-related cardiac pathologies including cardiac hypertrophy and fibrosis. The purpose of this study was to evaluate the eyes of mice overexpressing TMEM135 (Tmem135 TG) for ocular pathologies on two different murine genetic backgrounds.
Various aged male and female Tmem135 TG mice and wildtype (WT) littermates congenic on either the C57BL/6J (B6) background or the FVB/NJ (FVB) background (without the Pde6brd1 mutation) were used for this study. Visual function was assessed by electroretinography (ERG). Eyes were collected for histology, electron microscopy, immunohistochemistry and Western blot analysis.
We observed striking retinal pigmented epithelium (RPE) abnormalities in B6-Tmem135 TG mice beginning at one month of age. The phenotype consisted of larger and thinner RPE cells, displaced RPE cells within the photoreceptor outer segments, loss of the apical microvilli and basal infoldings, hypopigmentation, and vacuolization within RPE cells. Ultrastructural examination of the RPE revealed smaller mitochondria in these mice as previously observed in the cardiomyocytes of Tmem135 TG mice. These RPE changes precede retinal dysfunction, which was detected by decreased scotopic and photopic ERG responses in one-year-old B6-Tmem135 TG mice. Remarkably, no RPE abnormalities were detected in the FVB-Tmem135 TG mice.
Overexpression of TMEM135 causes pathologies characteristic of RPE atrophy often seen in late ‘dry’ age-related macular degeneration. These RPE pathologies are similar to the RPE phenotypes of mouse models of mitochondrial dysfunction and support a role of TMEM135 in maintaining mitochondrial homeostasis. Phenotypic difference between B6-Tmem135 TG and FVB-Tmem135 TG mice indicates the existence of genetic modifier(s). Identification of genetic modifiers will help uncover the role of TMEM135 in mitochondrial homeostasis. Our mouse model can be used to mechanistically interrogate the molecular pathways contributing to RPE atrophy development and elucidate therapeutic targets for late ‘dry’ age-related macular degeneration.
This is a 2020 ARVO Annual Meeting abstract.
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