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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

identified the derangement of amino acid homeostasis, histidine, leucine, and threonine were reduced in HD
such as alterations in tryptophan levels. 68,69 A study patients compared to healthy controls. These significant
employing liquid chromatography-high resolution mass changes in amino acid levels could serve as potential clinical
spectrometry-based metabolomics further revealed biomarkers. Moreover, another independent study utilizing
an altered amino acid profile in PD patients, alongside plasma and CSF samples for metabolomic analysis from
alterations in organic acids, steroids, and lipids. 70 HD patients and controls confirmed several differences
Interestingly, the gut microbiota has been in amino acid levels. In particular, levels of arginine and
reported to exert immunomodulatory effects through glycine were significantly increased and were associated
tryptophan catabolites, which attenuate the secretion of with disease progression, while a reduction in serine levels
was also reported.
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proinflammatory cytokines. In addition, serum analysis
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comparing amino acid profiles between PD patients and In connection with amino acid metabolism, several
healthy individuals revealed significant differences in the independent studies observed decreased levels of
levels of alanine, arginine, phenylalanine, and threonine. BCAAs in both the plasma and CSF of HD patients. 77,79
Higher serum concentrations of these four amino acids have Alterations in BCAA homeostasis have been observed in
been positively correlated with shorter disease duration, other neurodegenerative diseases, indicating a common
suggesting a potential link to disease progression. 71 characteristic feature of neurodegeneration. The study
confirmed that different enzymes involved in BCAA
The roles of mTOR signaling and the GCN2-ISR synthesis are differentially expressed in the brain of the
pathway in metabolic signaling cascades that sense amino R6/2 mouse, an experimental model that mimics the
acid abundance or deprivation are well-documented. pathophysiology of HD.
mTOR signaling induces autophagy, an important
physiological cellular process responsible for protein Interestingly, cysteine metabolism, normally tightly
clearance and the maintenance of proteostasis within regulated by the key enzyme cystathionine γ-lyase
the cell. In the context of PD, this signaling cascade is (CSE) for its de novo synthesis, is also disrupted in
expected to be upregulated. Indeed, mTOR signaling has HD. This disruption affects signaling processes in the
been reported to be activated in the cortex of patients brain. In experimental mouse models of HD, significant
with α-synuclein accumulation, contributing to impaired downregulation of the CSE enzyme has been reported,
autophagy. Therefore, one potential therapeutic strategy leading to significantly lower cysteine levels. Therefore,
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could involve the use of mTOR inhibitors to enhance enhancing CSE production might confer adaptive benefits
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autophagy and mitigate the accumulation of neurotoxic in HD. Supporting this, another independent study has
protein aggregates in the CNS parenchyma. From another demonstrated that treatment with cysteine or N-acetyl-
perspective, the GCN2-ISR pathway also appears to play a cysteine helps restore cysteine balance, suggesting a
key role in disease progression. Although data are limited, potentially promising therapeutic approach. 78
it has been shown that activation of GCN2, mediated by Last but not least, concerning cellular metabolic
amino acid deficiency in the cellular microenvironment, signaling, mTOR signaling pathways are also affected in
leads to the activation of the ATF4 transcription factor. HD, as expected. It has been speculated that huntingtin –
ATF4, in turn, induces the expression of a specific subset the protein that, due to inborn errors in the DNA, becomes
of genes, including parkin. The induction of parkin in the toxic and causes brain damage – induces mTOR signaling.
substantia nigra, the brain region most affected by PD, This finding is further supported by evidence that depletion
has been associated with a lower risk of developing PD, of the huntingtin gene in experimental animal models
suggesting it may serve as a neuroprotective mechanism. 73 significantly attenuates mTOR activation. Additional
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studies have indicated that inhibition of mTOR exerts a
4.4. Amino acid metabolism in HD beneficial effect on disease progression by eliminating
As previously mentioned, HD is a disorder well-characterized toxicity mediated by CAG expansions through the
in terms of its pathophysiology and genetic cause, marked induction of autophagy. 80,81 To the best of our knowledge,
by profound neurodegeneration and subsequent axonal there is surprisingly no available data on the role of GCN2
loss. It has been speculated that disturbances in amino acid signaling in the context of HD and how it is regulated in
metabolism may contribute to the severe inanition in HD the framework of the pathological condition HD.
patients. Metabolomic studies have confirmed alterations
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in amino acid levels through the analysis of samples isolated 4.5. Amino acid metabolism in ALS
from HD patients and healthy individuals. Furthermore, In the context of amino acid metabolism in ALS, CSF
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the study indicated that plasma levels of asparagine, serine, metabolomics analysis has revealed decreased concentrations

Volume 3 Issue 3 (2024) 9 doi: 10.36922/gpd.3294