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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

For example, proteins such as HEXB, TREM2, and OFML3 T-cells and B-cells, have the ability to breach the blood-
are microglial markers that are abundantly expressed in brain barrier (BBB), invade the CNS parenchyma, and
the healthy brain. It has been established that microglia- provoke the release of pro-inflammatory cytokines and
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specific genes are differentially expressed not only under other substances. These substances, including proteolytic
health and pathological conditions but also that different enzymes, matrix metalloproteases, cytokines, oxidative
subsets of microglia can become activated depending on products, and free radicals, progressively lead to the
the disease state. In particular, a distinct microglial response destruction of axonal myelin sheaths. In addition, these
state known as disease-associated microglia (DAMs) has secretory molecules trigger the activation and subsequent
been identified in both mouse models of AD and human recruitment of other cells in the CNS, such as microglia
patients suffering from AD. These DAMs colocalize with and peripheral immune cells, further exacerbating the pro-
β-amyloid (Aβ) plaques, indicating their involvement in inflammatory microenvironment in the brain parenchyma.
the clearance of amyloid. This subset is characterized by The main clinical manifestations of MS include movement
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the increased expression of proinflammatory cytokines, disorders, selective memory impairment, extreme fatigue,
including major histocompatibility complex II, CD36, and cognitive disturbances. Accumulating evidence
IL-1, IL-6, and TNF. Besides, mutations in the gene suggests that B-cells are likely to be involved in the
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encoding for TREM2, a well-established microglial marker pathogenesis of MS. 21,22
in the steady state, have been associated with an increased
risk of developing AD. 14 The most prevailing characteristics of MS are multifocal
neuroinflammation, the formation of demyelinating
Likewise, perturbed cell metabolism is another plaques or lesions, and axonal degeneration, all of
well-established characteristic present in most which eventually lead to neuronal loss. Oligodendrocyte
neurodegenerative disorders. Cellular identity and function loss is another significant defect, and the presence of
have been closely linked to cellular metabolism. 15,16 oligoclonal bands in the cerebrospinal fluid (CSF) is a
Mitochondrial dysfunction, in particular, has been widely further diagnostic criterion for the underlying pathology.
reported in neurodegenerative disorders, highlighting One well-established mouse model used to study the
the important role of metabolism in disease progression. mechanisms driving MS pathogenesis is experimental
Specifically, impaired mitochondrial dynamics – reflected autoimmune encephalomyelitis, induced by immunization
in altered shape, size, and morphology – is a well- with the encephalitogenic 35 – 55 peptide of myelin
established hallmark in diseases such as AD, PD, and MS. oligodendrocyte glycoprotein in complete Freund’s
1
Moreover, mitochondria are known to be a central hub for adjuvant, followed by the administration of pertussis toxin
amino acid biosynthesis, indicating a close interrelation to disrupt BBB integrity.
between mitochondrial homeostasis and amino acid
metabolism. 17,18 At present, there is no specific cure for MS, despite
significant progress in basic and clinical research.
2. Neurodegenerative disorders However, many therapeutic agents are available that
focus on alleviating specific symptoms or treating
2.1. MS
acute attacks, thereby improving patients’ quality of
Among neurodegenerative diseases, one of the most life. Monoclonal antibodies such as natalizumab and
representative and widely known is MS, a chronic ocrelizumab, and disease-modifying therapies that exert
autoimmune inflammatory disorder of the CNS immunomodulatory effects on the damaged brain are the
characterized by myelin degeneration, neuroinflammation, most widely used drugs for managing MS. 22,23 Current
and axonopathy. Although MS is generally marked by research is also focusing on the development of drugs that
a complex and poorly understood pathophysiology modulate immune metabolism in T-cells or B-cells to more
with broad heterogeneity, it is well-established that both effectively tackle MS, pinpointing immunometabolism
environmental factors and genetic susceptibility contribute dynamics in the progression of the autoimmune disease.
to the disease phenotype and potentially trigger immune
responses. Emerging evidence also supports the role of 2.2. AD
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epigenetic alterations as an important contributing factor AD is one of the most common neurodegenerative diseases,
to disease onset. Specifically, these epigenetic mechanisms primarily affecting the elderly and leading to progressive
include DNA methylations, histone modulations, and the memory loss, which is commonly known as dementia.
regulation of microRNAs. 20 AD can be distinguished into two distinct categories:
In regard to disease pathology, it has been demonstrated sporadic and familial. Sporadic AD, which accounts for
that infiltrating macrophages, along with autoreactive approximately 90 – 95% of cases, typically presents with

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