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Marin Gantner, Martina Wallace, Regis Fallon, Michal Handzlik, Kevin Eade, Ilham Polis, Alex Ideguchi, Maki Kitano, Christian Metallo, Martin Friedlander; Reduced systemic serine levels lead to retinal defects in a mouse model of MacTel. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4954.
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Macular telangiectasia type II (MacTel) is a late age-of-onset macular disease that leads to progressive vision loss. While no single causative gene is known, sera metabolomics revealed that MacTel patients have reduced circulating serine and glycine levels. These amino acids are central to many metabolic pathways including nucleotide, protein and lipid synthesis. How reduced serine and glycine levels might lead to retinal degeneration is unknown.
To test the rate of serine and glycine biosynthesis, as well as enrichment from the circulation, we used heavy carbon (C13) labeled glucose, serine or glycine coupled with mass spectrometry to trace the path of these metabolites in vivo. To determine the consequences of reduced circulating serine and glycine levels mice we fed diets lacking these two amino acids and their subsequent metabolite levels and visual function were monitored.
We determined that the neural retina and RPE/choroid have high de novo serine synthesis, almost matching that of the brain. Additionally, a large portion of the serine in the retina is taken up from circulation. Glycine synthesis and uptake rates are relatively low in the retina. Mice fed a diet deficient of serine and glycine had reduced circulating levels of these amino acids and increased levels of atypical lipids associated with low serine. ERG measurements indicated visual impairment.
The high rate of serine biosynthesis as well as uptake from the circulation suggests that the serine pool in the retina is highly dynamic. Reducing circulating serine and glycine levels, as observed in MacTel patients, is sufficient to generate lipid defects and drive retinal dysfunction.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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