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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

of the amino acids arginine, serine, and threonine in ALS restoring proteostasis. Notably, in all the neurodegenerative
patients harboring the D90A mutation in the SOD1 genein, disorders discussed, mTOR activation was correlated
compared to healthy controls. Metabolomic profile analysis with disease progression, with the exception of AD,
of samples from ALS patients has also revealed alterations in where outcomes were more controversial. Likewise, the
amino acid metabolism, primarily in the pathways involving GCN2-ISR pathway exhibits a complex relationship with
arginine and proline, which were positively associated with the progression of neurodegenerative disorders, which
disease progression. In addition, changes were observed in remains to be further elucidated. Specifically, while GCN2
the metabolism of tryptophan and BCAAs. Arginine and activation has been reported to exhibit neuroprotective
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proline metabolism are emerging key pathways implicated in effects in experimental mouse models of MS, PD, and AD,
ALS pathophysiology, as indicated by metabolomic studies it appears to have opposite effects in ALS. Surprisingly, to
involving ALS patients. These findings were in alliance the best of our knowledge, there is no available evidence
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with another interesting report stating that supplementation regarding the role of GCN2 in HD, highlighting a potential
with L-arginine in a transgenic mouse model of ALS area for future research.
harboring the G39A mutation in the Sod1 gene provided Metabolomic studies analyzing amino acid profiles from
neuroprotective effects and contributed to hindering disease CSF and blood samples of patients with neurodegenerative
progression. 84
disorders, compared to healthy controls, revealed common
Moreover, tryptophan levels have been reported to be patterns of disturbed amino acid concentrations in
decreased in both the cerebral cortex and plasma of ALS immune cells. Specifically, these studies reported that
patients compared to healthy individuals. 85,87 In contrast, (i) arginine levels were decreased in MS, PD, and ALS,
glutamate – a key amino acid metabolite – has been found (ii) reduced levels of BCAAs were observed in AD and
to be elevated in both CSF and blood samples from ALS HD, (iii) threonine concentrations were decreased in PD,
patients, a finding that has been consistently confirmed by HD, and ALS patients, and (iv) despite these common
numerous independent research studies. 86-88 disruption in amino acid levels, each neurodegenerative
The role of amino acid signaling cascades in ALS disorder exhibited a distinct metabolic signature in terms
pathogenesis is also under investigation, particularly of amino acid concentrations, which could help alleviate
regarding their contribution to disease progression. problems in differential diagnosis arising from overlapping
Specifically, activation of mTOR signaling in astrocytes changes in amino acid levels in differential diagnosis
has been associated with the inhibition of the autophagy arising from overlapping changes in amino acid levels. It
pathway, while inhibition of mTOR reduces astrocyte is important to note, however, that heterogeneity in amino
reactivity and mitigates further toxicity in motor neurons. acid levels among patients may occur mainly attributed
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Interestingly, induction of the ISR signaling pathway has to variations in individual nutritional status. Therefore,
been identified as a molecular hallmark of ALS. Notably, metabolomics studies should include large cohorts of
silencing of GCN2 not only attenuated neurotoxicity but patients to ensure that these variations are accounted for.
also rescued the neuronal death phenotype, suggesting a Collectively, these data suggest a new avenue for addressing
critical role in disease modulation. and managing neurodegenerative diseases. This approach
could also have applications in the treatment of acute
5. Discussion disseminated encephalomyelitis, neuromyelitis optica
spectrum disorder, and other rare neurological diseases.
The aim of the present review was to provide a logical
framework for understanding the potential regulatory However, it is important to consider that metabolomic
role of amino acid metabolism in the context of data represent only a specific snapshot of molecular events
neurodegeneration and to provide a broad overview of within cells, which may vary significantly among individual
disrupted amino acid metabolism. This discussion focuses patients due to the broad heterogeneity of these diseases.
on the most common and representative disorders of the In addition, amino acid fluctuations can differ depending
CNS, which have disastrous consequences on the patients’ on the disease state and progression. A notable limitation
quality of life. A key finding is the well-documented of this review is its focus on metabolomic studies based
upregulation of the mTOR signaling pathway across the primarily on blood samples rather than CSF samples,
neurodegenerative diseases reviewed. Pharmacological due in large part to the relative ease of blood collection
inhibition of the mTOR signaling pathway has shown compared to CSF sampling. Future research should aim
beneficial effects in each case. This capacity can be attributed to include more CSF-based studies to provide a more
to the fact that inhibiting mTOR induces autophagy, which comprehensive understanding of the metabolic alterations
facilitates the clearance of protein aggregates, thereby associated with neurodegenerative diseases.

Volume 3 Issue 3 (2024) 10 doi: 10.36922/gpd.3294