Our long-term goal is to understand the molecular mechanisms causing retinal defects associated with human retinal diseases and aging. Recent studies have shown that similar synaptic abnormality and gradual photoreceptor cell loss are commonly observed in aging and a number of retinal degenerative diseases. The similarity of retinal abnormalities observed in aging and age-dependent retinal degenerative diseases suggests the link between molecular mechanisms underlying these conditions. Elucidating the molecular mechanisms causing the common age-dependent retinal abnormalities, therefore, should enhance our understanding of age-dependent retinal diseases and aging of the retina. We identified an ENU-induced mutant mouse strain, FUN025, showing early onset of age-dependent abnormalities in the retina. The phenotypes of these mice mimic abnormalities that are observed in normal aging retina, but they appear at the earlier time point. Furthermore, we found that the retina of FUN025 mice is more susceptible to oxidative stress, suggesting that the FUN025 gene is involved in protection of photoreceptor cells from oxidative stress. Following genetic mapping of the FUN025 mutation, we found a splice-site mutation in the transmembrane protein 135 (Tmem135) gene that is in the minimal FUN025 region. We further determined that the TMEM135 protein is localized to mitochondria as well as synaptic vesicles of photoreceptor cells, and its expression is reduced in the normal aging retina. Mitochondria are known as both the source and the target of oxidative damage in cells, as well as the mediator of apoptotic cell death, and are the likely organelle affected by the FUN025 mutation. These findings have led us to our hypothesis that FUN025 has a major role in the mitochondria to protect photoreceptor cells from oxidative stress. In this application, our major focus is to identify genes involved in age-dependent retinal abnormalities, and characterize those molecules. More specifically, in Aim 1, we will test Tmem135 as a strong candidate gene for FUN025, and definitively identify the gene responsible for FUN025 phenotypes.
In Aim 2, we will study the role of FUN025 in the mitochondrial functions and cellular responses to oxdative stress. In addition, we will test whether overexpression of the FUN025 gene provides greater protection of photoreceptor cells from oxidative stress.
In Aim 3, we will conduct positional cloning of the responsible gene for another mouse mutant showing age-dependent photoreceptor degeneration and synaptic abnormalities, that are identical to those observed in FUN025 mice. Completion of the proposed studies should provide multiple entry points into the molecular mechanisms underlying age-dependent retinal degeneration, and may offer therapeutic strategies for prevention of retinal conditions associated with aging and age-dependent retinal disorders.

Public Health Relevance

For age-dependent diseases to manifest themselves in an age-dependent manner, the process of aging and its associated cellular changes must play key roles. Using mouse models with early onset of age-dependent retinal degeneration and synaptic defects, we propose to determine the molecular mechanisms underlying theses conditions. This study may provide insights into how age-dependent changes interact with disease- causing mechanisms in the retina and offer therapeutic strategies for prevention of retinal conditions associated with aging and age-dependent retinal disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Shen, Grace L
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University of Wisconsin Madison
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United States
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Bhute, Vijesh J; Bao, Xiaoping; Dunn, Kaitlin K et al. (2017) Metabolomics Identifies Metabolic Markers of Maturation in Human Pluripotent Stem Cell-Derived Cardiomyocytes. Theranostics 7:2078-2091
Lee, Wei-Hua; Higuchi, Hitoshi; Ikeda, Sakae et al. (2016) Mouse Tmem135 mutation reveals a mechanism involving mitochondrial dynamics that leads to age-dependent retinal pathologies. Elife 5:
Higuchi, Hitoshi; Macke, Erica L; Lee, Wei-Hua et al. (2015) Genetic basis of age-dependent synaptic abnormalities in the retina. Mamm Genome 26:21-32
Maddox, Dennis M; Collin, Gayle B; Ikeda, Akihiro et al. (2015) A Mutation in Syne2 Causes Early Retinal Defects in Photoreceptors, Secondary Neurons, and Müller Glia. Invest Ophthalmol Vis Sci 56:3776-87