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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

HTT gene, which encodes the protein huntingtin, located It is speculated that ALS has a strong genetic component,
on chromosome 4. HD is the most common of the involving mutations in different genes such as superoxide
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nine identified poly-glutamine disorders. The huntingtin dismutase 1 (SOD1), fused in sarcoma, and chromosome
protein plays a crucial role in normal physiological 9 open reading frame 72, each contributing to a distinct
processes such as CNS development, axonal transport, and molecular and pathological signature. 35,36 The role of TDP-
synaptic function, pinpointing its significant importance 43 has been extensively studied over the last decades to
in maintaining neuronal homeostasis and function. Under delineate its exact mechanism in disease progression.
normal physiological conditions, the HTT gene contains At present, the only FDA-approved disease-modifying
approximately 10 – 35 tandem repeats of the trinucleotide, therapy for ALS is riluzole. However, a broad spectrum
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which encodes the amino acid glutamine. This abnormal of symptomatic therapies is also used worldwide.
amplification of the sequence repetition has a direct effect Recently, another drug, edavarone, has been approved by
on the tertiary structure of the protein, eventually leading the FDA and has been shown to slow the advancement of
to the accumulation of misfolded protein aggregates that ALS. Despite these medications, they primarily focus on
are neurotoxic. In addition, the progression and severity of symptom relief and prolonging patients’ overall survival,
the disease largely depend on the length of the trinucleotide highlighting the immense need for more precise and
sequence repetition. effective therapies.
Common symptoms of HD include mild motor, 3. Amino acid signaling and metabolism
mental, and cognitive disturbances, which become more
pronounced over time. Notably, adult-onset HD, which 3.1. The role of amino acids in cellular homeostasis
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is the most common subtype, classically manifests around Cell metabolism comprises a complex network of
40 years of age with a wide range of motor, cognitive, and intracellular biochemical reactions that ultimately
psychiatric disturbances. Interestingly, increased levels of lead to the production of metabolites. These metabolic
reactive microglia and proinflammatory responses have intermediates are actively involved in fundamental
been reported in the brains of HD patients in comparison biological processes, all of which coordinate effectively to
to healthy individuals. Although the cause of HD is promote cell survival. These biochemical reactions can be
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well-characterized, there is currently no standard cure. broadly classified into catabolic and anabolic pathways,
Therapeutic agents primarily aim to eliminate specific each playing a crucial role in maintaining cellular integrity
symptoms of the disease rather than address the underlying and ensuring homeostasis at the organismal level. Catabolic
cause. pathways are responsible for the conversion of macro and
micronutrients into energy, whereas anabolic pathways are
2.5. ALS involved in the production of macromolecules. In particular,

ALS, also known as Lou Gehrig’s disease, is a fatal type of cell metabolism is essential for energy production, biomass
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motor neuron disease that affects both upper and lower synthesis, and redox homeostasis. In addition, metabolic
motor neurons in the brain and spinal cord, leading to products can promote both proinflammatory and anti-
severe symptoms such as paralysis. This clinical syndrome inflammatory responses. 39,40
is well-characterized by muscle spasticity and progressive Amino acids, which are the building blocks of protein,
muscle weakness. Nevertheless, ALS remains one of the constitute more than 60% of the cellular macronutrient
most complex diseases affecting the CNS due to its broad mass in mammalian cells. Amino acids play a fundamental
heterogeneity in biochemical, genetic, and clinical features. role in protein synthesis and also serve as cell signaling
There are two distinct forms of ALS: sporadic molecules and regulators of gene expression, particularly
(idiopathic) and familial. The sporadic form accounts in protein phosphorylation cascades. As a major category
for approximately 90% of all reported ALS cases. In of macronutrients that sustain life, amino acids can be
the familial form, a major pathological hallmark is the classified as either non-essential or essential, depending
presence of trans-activator regulatory DNA binding on whether the organism can synthesize them de novo or
protein 43 (TDP-43). TDP-43 is a nuclear protein involved must obtain them from the diet.
in RNA processing and metabolism, suggesting that RNA Amino acids contribute to a wide range of biological
dysregulation plays a key role in the pathogenesis of the processes, such as ATP generation, nucleotide exchange,
disease. Another characteristic pathological feature of and redox balance. 41,42 Amino acid sensing is mediated by
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ALS is the accumulation of ubiquitin-immunoreactive a complex network of dynamic players and is essential for
neuronal cytoplasmic inclusions, which are primarily communicating amino acid availability. Dysfunctions in
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distributed in motor neurons. amino acid availability, or deregulation in the components

Volume 3 Issue 3 (2024) 5 doi: 10.36922/gpd.3294