Serine and glycine physiology reversibly modulate retinal and peripheral nerve function

Abstract

Purpose : Macular telangiectasia type 2 (MacTel) is a neurodegenerative retinal disorder leading to loss of central vision. The genetic drivers of MacTel are complex, but converge on serine and glycine metabolism with patients sharing a systemic metabolic signature of low levels of circulating serine and glycine. In mice, reducing systemic serine and glycine levels leads to reduced retinal and peripheral nerve function. Why the effects of systemic disruption of serine and glycine metabolism manifest in the retina is not understood. Furthermore, the consequences of serine supplementation on retinal health have not been explored.

Methods : To characterize the metabolic pathways supporting serine homeostasis in the retina, we utilized metabolic tracing analyses in vivo and ex vivo and determined the expression pattern and protein localization of serine and glycine enzymes and transporters with qPCR and IHC. To test the reversibility of the serine-associated retinal and peripheral nerve phenotypes in mice, we aged the mice until phenotype onset and then supplemented them with dietary serine.

Results : We determined that the eye uniquely leverages diverse pathways to maintain serine and glycine levels, including synthesis from glucose (similar to brain), glycine cleavage (similar to liver and kidney), and transport from circulation of dietary and hepatic/renal supplies. Each of these pathways are further partitioned between tissue and cell types within the retina. Furthermore, oral serine supplementation reverses established, age-dependent retinopathy and peripheral neuropathy in mice.

Conclusions : The uniquely diverse mechanisms by which the retina obtains serine likely reflects the importance of serine for retinal function and may explain why a systemic reduction of serine manifests in the retina, as observed in MacTel. Given that aberrant serine metabolism has been documented in a range of age-related diseases such as diabetes, neurodegeneration, and cardiovascular disease, these findings suggest that restoration of serine homeostasis is a potential therapeutic approach not only for MacTel, but more broadly for age-related retinal health.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.