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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

affected patients. Emerging research evidence indicates This observation pinpoints the close association between
that these neurodegenerative disorders have not only a neurodegeneration and perturbed amino acid metabolism
genetic but also an epigenetic background. In addition, in the brain. Specifically, the accumulation of protein
1-3
environmental factors appear to play a significant, yet not aggregates is a common hallmark of neurodegenerative
fully understood, role in the onset of these neurological diseases and is considered a major contributor to disease
disorders. Notably, there is a broad spectrum of these progression, such as in Alzheimer’s disease (AD), where it
disorders, with symptoms ranging from mild-to-severe causes cytotoxicity and impedes normal neuronal survival.
disability, and current treatments are not efficient for Indeed, apart from multiple sclerosis (MS), which is an
all patients. Nevertheless, recent advancements in both autoimmune disorder, many neurodegenerative disorders
clinical and research settings have provided substantial are associated with the formation and accumulation of
insights into the underlying mechanisms, including the protein aggregates. However, it remains unclear to what
identification of signaling pathways that may be involved extent these aggregates are the main causative factors in
in the pathogenesis of neurological disorders. disease initiation, progression, and development, or if they
A major risk factor associated with neurodegeneration are merely a consequence of the disease. Furthermore,
is aging, a fundamental process primarily characterized by immune disturbances in other neurodegenerative disorders
epigenetic modification, genomic instability, proteostatic could play a key role in mediating disease development
impairment, and telomeric attrition, among other and disruption in the mechanisms of proteostasis.
hallmarks. Despite the strong association with aging, Another prevalent pathological feature in neurological
4,5
neurodegenerative disorders can affect individuals at any disorders is the disruption of autophagy, a highly
age, particularly those with a hereditary predisposition. conserved catabolic process responsible for degradation
In fact, these disorders may manifest early in life, even through a lysosome-dependent process. Disruptions in
8,9
during childhood, with symptoms ranging from mild the mechanisms that regulate apoptosis and autophagy
motor deficits and fatigue to severe cognitive impairment signaling pathways have been linked to the pathophysiology
and motor disability. Although there is no cure for of neurodegenerative disorders. 10
demyelinating disorders, several therapeutic agents Notably, impairment in autophagy signaling
have been approved by the United States food and drug mechanisms has been reported in several neuropathies,
administration (FDA) to alleviate clinical symptoms and such as AD, Parkinson’s disease (PD), Huntington’s disease
monitor disease progression. While each neurological (HD), and amyotrophic lateral sclerosis (ALS). Autophagy
disorder is well-characterized by specific pathological is known to decline with age, indicating that it is a potential
features and causes, they share some common molecular contributing factor in neurodegeneration. Interestingly,
and cellular features, such as neuroinflammation. in rare neurodegenerative diseases, mutations have been
In neurodegeneration, genomic instability is a major identified in elements of the autophagy machinery. In
11
characteristic. It leads to an increased susceptibility to addition, cellular senescence is emerging as a hallmark
genome damage and DNA mutations. Interestingly, of neurodegeneration. Senescence, characterized by
6
genome instability has also been reported in other permanent cell cycle arrest, hinders the potential
pathological diseases, such as cancer and aging, indicating regeneration of damaged tissues, not only in somatic cells
intriguing interconnections among different types of but also in adult stem cells. Numerous factors, such as
diseases. Specifically, genome instability may result from oxidative stress and neuroinflammation, have been shown
the accumulation of mutations in different regions across to induce senescence. 12
the DNA genome, ranging from genes to non-coding It is not surprising that in neurodegeneration
DNA regions. Another possible etiology is chromosomal conditions, microglia – the resident immune cells of the
abnormalities, which can be caused by endogenous brain – exhibit altered function and play a central role in
mechanisms and external factors, such as ultraviolet CNS physiology by exerting immunomodulatory effects
irradiation. through the secretion of chemokines and cytokines such
Another hallmark of neurodegenerative diseases is as tumor necrosis factor (TNF) and interleukin (IL)-1.
13
the occurrence of proteinopathies, which include protein Recent research has shown that specific microglial markers
misfolding and the formation of protein aggregates. may be upregulated or downregulated under steady-state or
7
The maintenance of cellular proteostasis is important for disease conditions, respectively. Moreover, these cells have
proper cellular function, and disruption of this process the capacity to dynamically switch their metabolic profile
may result in the accumulation of toxic, potentially depending on their surrounding microenvironment,
pathogenic proteins, leading to extensive neuronal damage. which can lead to either beneficial or detrimental effects.

Volume 3 Issue 3 (2024) 2 doi: 10.36922/gpd.3294