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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

range of experimental MS models, indicating that this were decreased in the hippocampus, cortex, and midbrain
pathway is highly implicated in disease pathogenesis and of the affected neurons.
progression. Furthermore, metabolomic studies involving Taking into consideration that glutamate is the
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large patient samples and control groups have revealed primary excitatory neurotransmitter in the brain, these
an association between circulating aromatic amino acids changes likely have significant effects on normal brain
and MS disease severity, with these amino acids present energy metabolism. On the contrary, the levels of alanine,
in MS peripheral blood and CSF-derived immune cells. aspartate, and glycine were reported to be elevated.
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These findings highlight distinct abnormalities in aromatic Another report has demonstrated metabolic derangements
amino acid metabolism, implying an altered balance in branched-chain amino acids (BCAAs) – including
of immunomodulatory metabolites, though the exact valine, leucine, and isoleucine – which may be key drivers
mechanisms remain unresolved. In terms of metabolomic in the pathogenesis of AD. These findings align with a
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studies, a recent study has shown that serum levels of metabolic network analysis of blood samples from AD
aspartic acid, arginine, and cysteine were significantly patients, showing that reduced BCAA levels correlate with
decreased in patients suffering from secondary progressive heightened disease progression and severity.
MS (SPMS) in comparison to control samples. In contrast,
the levels of alanine and serine were reported to be higher Pertaining to AD, there is ongoing debate about
in SPMS patients. 58,59 the precise regulatory role of the mTORC signaling
cascade. Some studies suggest that the upregulation of
Collectively, these data demonstrate that altered
amino acid metabolism is a well-established feature of mTORC is primarily responsible for cytotoxic effects,
possibly due to the inhibition of autophagy. However,
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MS, with variations observed even at different stages other studies argue that mTOR activation is necessary
of the disease, highlighting the multifactorial and for maintaining long-term potentiation and memory
complex pathophysiological mechanisms that orchestrate formation and may offer a protective role in Aβ
neurodegeneration. These insights into amino acid level neurotoxicity. Intriguingly, Aβ plaques interact with the
alterations could be exploited to identify new biomarkers CNS microenvironment, triggering microglial activation
and develop future diagnostic approaches. Nevertheless, and metabolic reprogramming – a process dynamically
further research is needed to gain a deeper understanding and tightly regulated by the mTOR signaling cascade and
of amino acid fluctuations and reduced catabolism, as well occurring primarily in the acute phase of the disorder. It
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as to develop effective drugs targeting pathways such as is speculated that microglial inflammation, mediated by
mTOR signaling and its downstream effectors.
Aβ deposition and accumulation, depends on the mTOR
4.2. Amino acid metabolism in AD signaling cascade, highlighting its immunomodulatory
role in neurodegenerative disorders.
AD is a complex pathophysiological neurological disorder
primarily attributed to perturbations of proper protein Another example of the interaction between metabolic
folding mechanisms, leading to the formation of protein signaling pathways and AD pathology is the regulatory
aggregates and subsequent neurotoxicity in the CNS. In role of the GCN2-ISR pathway. Specifically, GCN2 plays a
this context, amino acid metabolism plays a major role fundamental role in alleviating disease-related, long-lasting
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not only in the pathogenesis but also in the progression of synaptic plasticity. While the GCN2 cascade has been
the disease. Interestingly, a metabolomics study utilizing linked to neurodegenerative diseases, amino acid stress
high-resolution mass spectrometry on patient samples has not yet been reported as the primary cause of severe
was performed to characterize and identify metabolic neurological pathologies, in contrast to misfolded protein
alterations in transgenic CRND8 mice, which harbor a aggregation. Instead, it appears to modulate the disease
mutated form of the human APP gene. This mutation process, a topic currently under thorough investigation.
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leads to enhanced Aβ production and plaque deposition Intriguingly, GCN2 knockout fails to rescue memory
compared to healthy controls. In this experimental mouse deficits in AD mouse models.
model, the animals develop Aβ plaques, which become
evident and progress with age. The study revealed a 4.3. Amino acid metabolism in PD
divergent profile of tryptophan metabolism, reflected in PD is the second most common age-related
alterations to the kynurenine pathway, which is the primary neurodegenerative disorder, significantly affecting
route of tryptophan metabolism in the body – a finding the elderly population worldwide. Recent research
corroborated by another independent study. Similarly, suggests that peripheral changes, such as metabolomic
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the study demonstrated that in the CRND8 mouse derangements, might precede and contribute to the
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model, the amino acid levels of glutamate and glutamine pathogenesis of PD. For instance, the previous studies have

Volume 3 Issue 3 (2024) 8 doi: 10.36922/gpd.3294