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Gene & Protein in Disease Amino acid metabolism in neurodegeneration

late onset and is associated with a combination of genetic though various genetic causes have been identified.
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and environmental factors. Familial AD, on the other Notably, mutations in the gene that encodes for the protein
hand, is characterized by early onset and occurs in cases parkin are among the most common causes of autosomal
where a dominant gene is inherited, contributing to and recessive PD. 27,28 Parkin is an E3 ubiquitin ligase involved
accelerating the progression of the disease. This form of in protein degradation processes. Mutations in regulatory
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AD is attributed to mutations in specific genes. Although elements that control autophagy mechanisms can lead to
the exact cause and mechanism underlying AD are not disrupted cellular proteostasis, with consequences for
completely understood, the disease is most notably normal cellular functions in the brain.
characterized by the presence of neurofibrillary tangles From a pathophysiological standpoint, Lewy bodies,
(NFTs) and the accumulation of soluble Aβ plaques. NFTs, which are cytoplasmic inclusions containing misfolded
unlike Aβ plaques, which are located within the brain protein aggregates of α-synuclein within the brain,
and blood vessels, are typically found inside neurons. It are detected in the damaged area of neurons. These
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has been reported that phosphorylation of tau protein α-synuclein aggregates are believed to be crucial mediators
results in the formation of these tangles, although the in the progression of the disease, exhibiting neurotoxic
exact mechanism that triggers tau phosphorylation and effects, although their exact role remains to be fully
subsequent dissociation remains unidentified. NFTs are deciphered. Clinical manifestations and symptoms of
considered major contributors to the progression of AD, PD normally develop slowly over time, with dominant
resulting in progressive neuronal cell death and brain symptoms including hand tremors, slow movements,
atrophy, which is an irreversible and harmful condition. balance problems, stiffness, and cognitive deficits.
Beta-amyloid is a metabolic byproduct present in The exact cause of PD remains largely unknown,
the brain parenchyma. The formation of Aβ plaques yet, it likely involves both genetic and environmental
is attributed to the abnormal aggregation of amyloid factors. Current research efforts are focused on increasing
precursor protein (APP) as a result of improper cleavage dopamine levels in the brain as a treatment strategy. Age is
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by the γ-secretase enzyme. These plaques may also another significant contributing factor to the development
initiate an immune response, causing neuroinflammation of PD. Interestingly, PD has been observed to involve
that damages surrounding neurons, disrupts neuronal a more widespread pathology affecting different brain
signaling, and impairs memory. Notably, Aβ plaques can regions and can also impact non-dopaminergic neurons.
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also be deposited around blood vessels in the brain, leading To date, the precise mechanisms that trigger and drive
to cerebral amyloid angiopathy. However, the exact role of disease progression in PD remain unresolved. In terms of
Aβ plagues in the pathogenesis and progression of AD is therapeutic strategies, both basic and clinical researches
currently under thorough and careful reevaluation. 24,25 are currently focused on targeting and eliminating
Current therapeutic options for AD are limited to drug α-synuclein protein aggregates. However, there remains an
agents that provide only mild symptom relief. These drugs unmet clinical need for the development of highly efficient
can be classified into two major categories: cholinesterase drug agents that can slow the progression of the disease or
inhibitors and N-methyl-D-aspartate receptor antagonists. partially reverse its symptoms.
The development of effective therapeutic strategies
requires a better understanding of the underlying 2.4. HD
pathophysiological mechanisms involved. 19 HD is a well-known autosomal dominant
neurodegenerative disease that primarily affects the basal
2.3. PD ganglia, especially the striatum and cortex, among other
PD is the second most common age-related brain regions. In HD, brain cells are severely damaged,
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neurodegenerative disorder after AD, characterized by a leading to progressive brain atrophy, which is consistent
diverse set of symptoms, including tremors and depression. with the occurrence of behavioral, motor, and cognition
PD primarily affects neurons located in the substantia nigra, problems, ultimately culminating in death. In contrast to
a specific region of the midbrain, leading to decreased all the aforementioned neurodegenerative disorders, the
levels of dopamine. Dopamine is a neurotransmitter pathology of HD is well-understood and can be attributed
responsible for coordinating body movements, among to a single type of genetic mutation in a specific gene. The
other functions. In PD, dopaminergic neurons gradually symptoms of HD typically emerge during middle age
die, resulting in the development of motor dysfunctions and include movement disorders and cognitive deficits.
and mental disabilities. The multifactorial and complex HD is primarily caused by a pathological expansion of
etiology of PD in most patients remains to be deciphered, 5’CAG3’ trinucleotide tandem repeat in exon 1 of the

Volume 3 Issue 3 (2024) 4 doi: 10.36922/gpd.3294