The Amino Acid-Neurodegeneration Axis: Excitotoxicity and Oxidative Stress as Context-Dependent Amplifiers of...

Homeostasis of amino acids is essential for the integrity of the CNS, and is maintained by a tightly regulated transport and metabolic circuit that ensures efficient neurotransmission, mitochondrial bioenergetics and redox homeostasis. Disruption of this equilibrium is associated with the pathogenesis of the major neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Excessive glutamatergic stimulation and impaired glycine or homocysteine metabolism result in pathological Ca²⁺ influx, loss of mitochondrial membrane potential and production of reactive oxygen species, which are hallmarks of these disorders. It also limits cysteine availability and causes glutathione depletion, which affects antioxidant defence, and disrupts tryptophan-kynurenine metabolism, further affecting neurotoxic and neuroprotective signalling. Though there are disease-specific molecular triggers, the convergent pathogenesis of metabolic disruption makes neurons susceptible to disease. The convergent pathways link amino acid dysregulation to the reinforcement of each other's mechanisms of excitotoxicity, oxidative stress, mitochondrial dysfunction, and protein aggregation. Correcting the amino acid balance has clear translational potential for developing new therapies, such as glutathione augmentation, modulation of NMDA receptors, targeting of transporters, and regulation of metabolic enzymes. In addition, the use of metabolic biomarkers alongside neuroprotective endpoints in clinical trials could improve detection rates, patient stratification, and therapeutic precision. The concept of amino acid metabolism as a mechanism of neurodegeneration, therefore, provides a systems-level perspective and targets potential areas for continued neuroprotection and disease modification.