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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

Figure 1. Schematic illustration of the two amino acid-sensing signaling pathways that are activated depending on the availability of amino acids in the
surrounding microenvironment: The mechanistic target of rapamycin and the general control non-derepressible 2 pathways. Figure generated using the
BioRender software.

in the recovery and reversal of memory deficits, suggesting immune responses. These effects are mediated by two
that targeting this pathway could offer a promising strategy distinct yet interrelated pathways: the mTOR pathway,
for addressing age-related neurodegenerative disorders. 52 which responds to amino acid abundance, and the GCN2-
ISR signaling cascade, which is activated by amino acid
4. Amino acid metabolism in deficiency, along with other triggering factors. 55
neurodegenerative disorders Interestingly, research has shown that the levels of
4.1. Amino acid metabolism in MS enzymes involved in tryptophan and arginine catabolism
– indoleamine 2,3 dioxygenase and arginase, respectively
As previously mentioned, MS is a neurological disorder – are significantly lower in MS patients in comparison to
characterized by the infiltration of autoreactive T-cells, healthy individuals. In addition, the study demonstrated
such as Th1 or Th17 effectors, into the CNS parenchyma that the mTOR signaling pathway was induced in
due to the disruption of BBB. In addition to T-cells, peripheral blood mononuclear cells isolated from MS
B-cells are also implicated in MS, where they contribute patients, confirming reduced amino acid catabolism in
by secreting autoantibodies and presenting antigens to these patients. Importantly, in myelin oligodendrocyte
T helper cells. These immune cells have high metabolic glycoprotein-induced experimental autoimmune
21
demands for amino acids to maintain their metabolism and encephalomyelitis GCN2 knockout mice, there were
ensure cellular homeostasis. Notably, it has been suggested elevated levels of Th1- and Th17-related cytokines, and the
that amino acid catabolism within these immune cells mice failed to develop the remission phase of the disease.
contributes to overall immune-mediated homeostasis, and It was also shown that activation of GCN2 resulted in the
perturbations in this catabolism have been observed in restriction of Th1 cell differentiation in both mice and
neurodegenerative disorders. 53,54 humans. 56
In MS patients, amino acid catabolism is remarkably With respect to amino acid-sensing pathways, the exact
decreased, leading to two major key outcomes: first, the contribution of amino acid availability to mTOR activity in
induction of proinflammatory responses through the neurodegenerative diseases remains to be fully unraveled.
secretion of specific cytokines, and second, a reduction in However, pharmacological inhibition of mTOR signaling
T regulatory cells, which are responsible for dampening has been reported to exert neuroprotective effects in a broad

Volume 3 Issue 3 (2024) 7 doi: 10.36922/gpd.3294