Serine and Glycine Physiology Reversibly Modulate Retinal and Peripheral Nerve Function

Reversible Regulation of Retinal and Peripheral Nerve Function: Physiological Study of Serine and Glycine

Background and Research Motivation

Macular Telangiectasia Type 2 (Mactel) is an age-related retinal disease characterized by central vision loss. The molecular etiology of this disease is complex and is primarily associated with the metabolism of serine and glycine. Many Mactel patients exhibit systemic metabolic abnormalities, presenting as reduced levels of serine and glycine in the serum. Furthermore, the metabolic characteristics of Mactel are similar to those of diabetes, both of which can lead to retinal degeneration, albeit with different pathological manifestations.

Recent studies have identified genetic variations related to serine and glycine metabolism in Mactel patients, exacerbating the deficiency of serine in the serum. At the same time, disruptions in serine metabolism are also linked to various age-related diseases such as neurodegenerative diseases and cardiovascular diseases. Therefore, understanding and restoring serine homeostasis in the body is of significant importance for improving related diseases. This study explores how the flow of serine, glycine, and one-carbon metabolism between the retina, liver, and kidneys maintains the balance and function of amino acids in the retina, particularly focusing on whether dietary regulation of serine levels can reverse retinal and peripheral nerve degeneration in mice.

Research Team and Publication Information

This paper was completed by Dr. Esther W. Lim, Dr. Regis J. Fallon, and others, primarily affiliated with the Salk Institute for Biological Studies, the University of California, San Diego, and the Lowy Medical Research Institute. The paper was published in the October 2024 issue of “Cell Metabolism” journal, available as open access.

Research Procedure

Research Subjects and Experimental Design

Researchers employed a combination of animal models and clinical samples to thoroughly investigate the production, source of serine, and its impact on retinal function. Specifically, the study comprises the following procedural parts:

  1. Animal Model Design: The study used Phgdh gene heterozygous knockout mouse models, which simulate the insufficiency in serine production found in Mactel patients. The research team divided the mice into two groups: one fed a normal diet, and the other on a serine/glycine-deficient diet, to assess the impact of serine deficiency on the retina.

  2. Isotope Tracing Experiment: Using stable isotope-labeled serine and glycine ([u-13C3]serine and [u-13C2]glycine), the study investigated the metabolic pathways of serine in the retina, liver, and kidneys. Mass spectrometry was used to measure the source of serine in the retina, revealing its reliance on different metabolic pathways.

  3. Retinal Function Test: Scotopic electroretinography (ERG) was conducted to measure the retinal response under different dietary conditions, evaluating the impact of serine deficiency on retinal function.

  4. Verification of Reversibility of Neural Damage: To verify the therapeutic effect of serine supplementation, after 12 months on the serine/glycine-deficient diet, mice were switched to a serine-supplemented diet, and recovery of retinal and nerve function was re-assessed.

Data Analysis Methods

The research team accurately analyzed the levels of amino acids and their metabolites in tissues and serum using mass spectrometry and molecular markers. In addition, real-time quantitative PCR was used to detect the expression levels of related genes in the retina to further elucidate the role of serine metabolism in the retina. Retinal cells were also subjected to immunofluorescence staining to verify the expression patterns of key molecules in serine transport and synthesis.

Main Research Results

1. Characteristics of Systemic Changes in Serine and Glycine Metabolism

The study found that Mactel patients have significantly reduced levels of serine and glycine in their serum, accompanied by an increase in specific deoxysphingolipids (doxsls) levels, reflecting an imbalance in serine metabolism. Patients with Phgdh gene variations exhibited a more severe deficiency in serine, indicating that haploinsufficiency of this gene exacerbates metabolic defects.

2. Source of Retinal Serine

Through stable isotope tracing studies, it was found that retinal serine primarily originates from blood circulation, and dietary supplementation of serine can significantly increase the levels of serine in the retina. The source of glycine in the retina mainly depends on the supply from organs such as the liver and kidneys, showing the retina’s high dependency on exogenous serine.

3. Aggravated Retinal Deficiency Due to Phgdh Gene Deletion

Under a serine/glycine-deficient diet, Phgdh heterozygous knockout mice showed significant reductions in retinal function, demonstrated by decreased b-wave amplitude in electrophysiological tests. These defects were improved upon feeding with supplementary serine. Additionally, low serine levels led to the accumulation of abnormal sphingolipids (doxsls) in the retina and peripheral nerves, further confirming the role of serine metabolism disorder in neurodegeneration.

4. Reversible Effects of Serine Supplementation

In dietary recovery experiments, mice supplemented with high serine showed significant recovery in retinal function, and the sensory function of the peripheral nerves was also improved. This indicates that the retinal and neural damage caused by serine deficiency may be reversible, rather than an irreversible neurodegenerative condition. Furthermore, serine supplementation effectively reduced doxsls levels in tissues and serum, further supporting the therapeutic potential of serine.

Research Conclusion

This study demonstrates that serine metabolism plays an important role in maintaining retinal and peripheral nerve health. The retina primarily relies on the serum level of serine, with locally synthesized serine serving only as a supplementary source. When serine is insufficient, haploinsufficiency of Phgdh will exacerbate metabolic defects and accelerate the development of retinal degenerative diseases. Supplementing serine can reverse retinal and peripheral nerve functional damage caused by metabolic abnormalities. Therefore, for serine deficiency-related diseases such as Mactel, serine supplementation might offer an effective therapeutic strategy.