Ornithine Metabolism in Neurodegenerative and Retinal Disorders

Ornithine occupies a pivotal junction in amino acid and nitrogen metabolism, linking the urea cycle, polyamine biosynthesis and neuroactive pathways. The mitochondrial enzyme ornithine aminotransferase (OAT) catalyses the reversible conversion of ornithine and α-ketoglutarate into glutamate-5-semialdehyde and glutamate, thereby regulating cellular levels of ornithine, glutamate and downstream metabolites such as γ-aminobutyric acid (GABA) and proline. Disruption of OAT activity yields hyperornithinaemia, a hallmark of gyrate atrophy of the choroid and retina, manifesting as progressive vision loss and eventual blindness. Beyond ocular pathology, altered ornithine flux has been implicated in central nervous system dysfunction; accumulation of ornithine and its derivatives can promote excitotoxicity, oxidative stress and dysregulated polyamine signalling, all features shared by neurodegenerative diseases including Alzheimer’s and Parkinson’s. The interplay between systemic and tissue-specific pools of ornithine underscores both the global and local consequences of OAT perturbation. Recent advances span from molecular dissection of disease-causing OAT variants through to translational strategies such as liver-directed gene therapy and tailored dietary manipulation. Together, these efforts highlight the enzyme’s dual role as a metabolic gatekeeper and therapeutic target, reflecting the wider significance of ornithine homeostasis in health and disease.

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Ornithine Metabolism in Neurodegenerative and Retinal Disorders publication trend

The graph below shows the total number of articles in ornithine metabolism in neurodegenerative and retinal disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Ornithine aminotransferase (OAT): Mitochondrial enzyme that transfers the δ-amino group of ornithine to α-ketoglutarate, producing glutamate-5-semialdehyde.

Hyperornithinaemia: Elevated concentration of ornithine in blood and body fluids, often due to OAT deficiency.

Adeno-associated virus (AAV) vector: Genetically engineered virus used for safe and sustained delivery of therapeutic genes to target tissues.

Pyridoxal 5′-phosphate (PLP): Active form of vitamin B6 that serves as a cofactor for aminotransferase reactions.

Gyrate atrophy: Rare autosomal recessive chorioretinal degeneration caused by loss of OAT activity, leading to progressive vision loss.

References

1. Liver‐directed gene therapy for ornithine aminotransferase deficiency. EMBO Molecular Medicine (2023).
2. Biochemical and Bioinformatic Studies of Mutations of Residues at the Monomer–Monomer Interface of Human Ornithine Aminotransferase Leading to Gyrate Atrophy of Choroid and Retina. International Journal of Molecular Sciences (2023).
3. Clinical, biochemical and molecular analysis in a cohort of individuals with gyrate atrophy. Orphanet Journal of Rare Diseases (2023).
4. Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways. Biology (2017).