Abstract
Purpose :
Macular telangiectasia type 2 (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; however, the mechanism by which low serine and glycine drives disease progression is unknown. We evaluated the impact of serine and glycine deprivation on the mouse retina transcriptome to better understand how availability of these non-essential amino acids contribute to retinal degeneration.
Methods :
To model the impact of reduced circulating serine and glycine on ocular tissues in disease onset, we placed mice on a control or serine- and glycine-deplete diet for 2 months. This time point was selected because it precedes onset of ERG impairment. We then conducted bulk-RNA sequencing on the retina and RPE/choroid and performed gene and pathway enrichment analyses to gain insight into the networks of genes altered.
Results :
We found that the retinal transcriptome of mice after 2 months on a serine- and glycine-free diet is minimally impacted. In contrast, the transcriptome of the RPE/choroid is highly disrupted by the deplete diet, with nearly 10% being significantly altered. Gene enrichment and pathway analyses of the RPE/choroid indicate cell signaling, carbon and lipid metabolism, and phagocytosis functions are dramatically altered by a serine and glycine free diet.
Conclusions :
The RPE/choroid is highly impacted by serine and glycine restriction prior to onset of retinal dysfunction. Transcriptome changes indicate dysregulation of numerous RPE/choroid pathways crucial to RPE function and closely linked to retinal metabolic homeostasis. These data illustrate that the RPE/choroid is highly sensitive to altered serine and glycine availability and suggest this tissue may be contributing to MacTel pathogenesis.
We would like to thank the Lowy Medical Research Institute for generously funding this research.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.