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Global Translational Medicine Parkinson’s: From cause to cure

by related behavioral impairments. Findings from these treatment strategies targeting oxidative stress have yet
models revealed that α-syn and tau co-pathology initially to achieve success in clinical trials. However, a deeper
manifest in the gut, followed by propagation to the dorsal understanding of PD-related gene products and oxidative
motor nucleus of the vagus or the nucleus of the solitary stress response mechanisms offers potential avenues for
tract, and subsequently to other brain regions. This novel treatment strategies. Future research should focus
progression was associated with behavioral deficits in on further elucidating these mechanisms to develop more
SYN103 and/or TAU368 transgenic mouse models. 19 effective neuroprotective strategies for PD.
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In summary, α-syn plays a central role in the 2.5. Mitochondrial dysfunction
pathophysiological processes of PD. It serves not only as
a biomarker for disease diagnosis but is also intricately Mitochondria, as the center of cellular energy metabolism,
connected to the disease’s pathogenesis and therapeutic play a critical role in maintaining neuronal health,
strategies. and their dysfunction can severely impact the nervous
system. Studies have pointed out that mitochondrial
2.4. Oxidative stress damage is associated with various neurological diseases,
Oxidative stress refers to a state of cellular damage including PD, Alzheimer’s disease, Huntington’s disease,
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resulting from an imbalance between the generation of and amyotrophic lateral sclerosis. The abnormal
reactive oxygen species (ROS) and the body’s antioxidant aggregation of α-syn, a hallmark pathological feature of
defenses. The brain, due to its high metabolic activity, is PD, impairs the dynamic balance of mitochondria. When
particularly vulnerable to oxidative stress. Numerous α-Syn aggregates abnormally, it impairs mitochondrial
central nervous system diseases, such as PD, Alzheimer’s motility and alters axonal transport. This disruption in
disease, Huntington’s disease, and ischemic diseases, are mitochondrial transport can result in energy deficits and
associated with oxidative stress. 20 increased oxidative stress, further exacerbating neuronal
damage. 26,27 Furthermore, a decline in the clearance
Oxidative stress is considered a critical factor in
the development of PD, with key sources including capacity of the autophagy-lysosome system can contribute
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mitochondrial dysfunction, dopamine metabolism, and to the abnormal aggregation of α-syn.
neuroinflammation. Mitochondrial abnormalities lead Proteins encoded by PD-related genes, such as PARKIN,
to ROS production and disrupt calcium homeostasis, PINK1, and DJ-1, are involved in mitochondrial metabolic
ultimately leading to neuronal apoptosis. Pathogenic pathways. These genes play a role in mitophagy, the
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gene products associated with PD, such as DJ-1, PINK1, selective degradation of damaged mitochondria. Impaired
Parkin, α-syn, and LRRK2, affect mitochondrial function mitophagy leads to increased ROS generation, which
in complex ways, leading to increased ROS production and exacerbates neuronal damage. 26
increased susceptibility to oxidative stress. Dysfunctions Mitochondrial dysfunction is a key factor in the
in these gene products impair mitochondrial clearance, pathogenesis of PD and holds significant potential for
further exacerbating oxidative stress. 21
the development of new therapeutic strategies. Further
In addition, oxidative stress is closely linked to research is needed to elucidate the complex interactions
neuroinflammation. By affecting the ubiquitin-proteasome between mitochondrial dynamics, oxidative stress,
system and mitophagy, oxidative stress promotes the and neuroinflammation in PD. Understanding these
accumulation of ROS, forming a vicious cycle that mechanisms is crucial for designing targeted therapies
intensifies neuronal damage. 21,22 Studies have also pointed aimed at preventing or reversing the progression of this
out that oxidative stress contributes to PD through the debilitating disease.
MHC-I pathway. In SH-SY5Y cells treated with 1-methyl-
4-phenylpyridinium, silencing PINK1 via specific 2.6. Environmental and genetic factors
small interfering RNA resulted in increased MHC-I Approximately 5 – 10% of PD cases are monogenic inherited
expression, indicating that oxidative stress may regulate diseases, highlighting the significant role of genetic
MHC-I expression through the PINK1 pathway, thereby susceptibility in the pathogenesis of PD. Researchers have
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contributing to PD onset. 23 developed methods to enrich and perform transcriptomic
Moreover, ROS production in cells is regulated by analysis of dopaminergic neurons from PD patients and
LRRK2 kinase, further underscoring its role in oxidative control groups, identifying 10 distinct dopaminergic
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stress-related processes. Despite the central role of neuron subpopulations. Using the Slide-seq technology,
oxidative stress in PD pathogenesis and its involvement the spatial localization of these subpopulations within the
in various cellular processes and molecular pathways, SNpc was determined, revealing that the SOX6_AGTR1

Volume 3 Issue 4 (2024) 4 doi: 10.36922/gtm.5082