Abstract
Purpose :
MacTel is a macular degenerative disease characterized by low circulating levels of the amino acids serine and glycine. Serine and glycine are central to many metabolic pathways important in retinal function and low serine is known to lead to the elevation of toxic lipids. Serine can be derived from several sources, including the glycine cleavage system (GCS). The GCS is comprised of four enzymes that drive the conversion of glycine to serine within the mitochondria of cells. The purpose of this study was to determine the relevance of the GCS in retinal metabolism and disease.
Methods :
To determine if the GCS was present in the retina, we analyzed transcript and protein levels of GCS components in wild-type mouse retinas using quantitative PCR and immunohistochemistry. To test the activity of the pathway, we infused mice with a heavy-labeled glycine and measured labeled serine (a GCS product) in the retina using mass spectrometry. Analysis of MacTel patient whole exome sequencing data was used to identify rare coding variants in the four GCS genes. Amino acids and sphingolipid levels were quantified in patient sera using mass spectrometry.
Results :
All four enzymes of the GCS are expressed in the retina, and one, glycine decarboxylase (GLDC), is highly enriched in the retinal pigment epithelium. In addition, heavy isotope tracing revealed that GCS is active in the retina, with a significant fraction of retinal serine being derived from the labeled glycine. Coding variants in GCS genes predicted to impact protein function were identified in MacTel patients. Interestingly, this subpopulation of patients has even lower levels of serine and glycine and higher levels of toxic lipid species than the broader MacTel population.
Conclusions :
The glycine cleavage system is present and active in the retina. MacTel patients carrying potentially deleterious variants of the GCS appear to have more severe changes in metabolite levels suggesting the GCS might be relevant to retinal disease.
We would like to thank the Lowy Medical Research Institute for generously funding this research.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.