Page 10 - GTM-3-4

Global Translational Medicine Parkinson’s: From cause to cure

tangles, mitochondrial dysfunction, and inflammatory In addition, studies have identified a specific cleavage
responses. Clinically, PD manifests as a spectrum of motor of UNC5C at positions N467 and N547 by asparagine
2,3
symptoms, including tremors, bradykinesia, and rigidity, as endopeptidase (AEP) in the substantia nigra of PD patients,
well as non-motor symptoms, such as cognitive impairment, as well as in human α-syn transgenic mice, neurotoxin-
emotional disturbances, sleep disorders, and autonomic induced PD mouse models, and neurons derived from
dysfunction. PD not only significantly impairs patients’ daily pluripotent stem cells. This cleavage exhibits an age-
4
functioning and quality of life but also imposes significant dependent increasing trend and negatively correlates with
psychological and economic burdens on patients and their netrin-1 levels. Blocking netrin-1 induces the activation of
families. Current treatment options for PD encompass AEP and caspase-3, leading to the cleavage of the UNC5C
pharmacotherapy, surgical interventions, gene therapy, stem protein into pro-apoptotic fragments, which promotes
cell therapy, and traditional Chinese medicine, among others. apoptosis of dopaminergic neurons. 7
In clinical practice, a comprehensive treatment approach is In summary, these studies highlight diverse mechanisms
commonly adopted to slow disease progression and alleviate contributing to dopaminergic neuronal degeneration in
symptoms. Given the growing prevalence and complexity of PD, including the nuclear translocation of SIRT2, TREM-1-
PD, its pathogenesis and treatment strategies remain a hot
topic in the medical field. mediated interactions between microglia and neutrophils,
and the proteolytic cleavage of the UNC5C receptor. These
2. The pathogenesis of PD findings offer new perspectives for understanding the
pathophysiology of PD and suggest potential targets for
2.1. Dysfunction and loss of dopaminergic neurons the development of new therapeutic strategies.
The dysfunction and loss of dopaminergic neurons in the 2.2. Neuroinflammation
substantia nigra pars compacta (SNpc) plays a significant
role in the pathogenesis of PD. Their progressive Neuroinflammation, involving a variety of cells and
degeneration leads to motor impairments such as molecules such as microglia, astrocytes, T cells, and
bradykinesia, resting tremors, and muscle rigidity, which various inflammatory mediators, plays a decisive role
are hallmark features of PD. Although numerous studies in the progression of PD. Both pre-clinical experiments
have established a correlation between dopaminergic and clinical studies have provided substantial evidence
neuronal loss and PD, the underlying mechanisms remain supporting the involvement of neuroinflammation in
unclear. SIRT2, a nicotinamide adenine dinucleotide- PD. The development of PD is mediated by multiple
dependent protein deacetylase primarily localized in the inflammatory signaling pathways.
cytoplasm, regulates various cellular pathways through The nuclear factor kappa B (NF-κB) pathway, a
the deacetylation of multiple substrates. Research in critical nuclear transcription factor, is involved in diverse
cellular and animal models of PD has shown that SIRT2 pathophysiological processes, such as immune responses,
translocates from the cytoplasm to the nucleus, a process inflammatory reactions, and cell growth and death.
that promotes dopaminergic neuronal death. This nuclear NF-κB is expressed in all cells of the nervous system
translocation is facilitated by phosphorylation at Ser331 and regulates neuroinflammation by controlling the
and Ser335, mediated by cyclin-dependent kinase 5, expression of tumor necrosis factor (TNF), interleukin
which is essential for this process. The myeloid cell- 1, and monocyte chemoattractant protein-1. Research
5
8,9
specific triggering receptor 1 (TREM-1), expressed on the using in vivo CRISPR-Cas9 screening has identified
surface of microglia and neutrophils, has been implicated apoptosis induced by p53 activation, mediated through
in PD. Elevated levels of serum soluble TREM-1 in PD the TNF-α–NF-κB pathway, as a primary cause of
patients positively correlate with disease severity and
motor impairment intensity. In a subacute PD mouse dopaminergic neuronal loss. Furthermore, the TNF-α
model, microglial TREM-1 levels significantly increased inhibitor adalimumab has demonstrated significant
after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neuroprotective effects, increasing the survival of
(MPTP) injection. TREM1 knockout (KO) in these dopaminergic neurons and promoting functional
recovery in PD mouse models.
10
models provided neuroprotection and prevented MPTP-
induced dopaminergic neuronal death, likely through the Toll-like receptors (TLRs), as pattern recognition
inhibition of neutrophil infiltration and suppression of pro- receptors, serve as key triggers of innate immune
inflammatory cytokines. TREM-1 can further exacerbate inflammatory responses. Literature indicates that TLR4-
neuroinflammation by activating downstream spleen mediated immune inflammatory responses play a
tyrosine kinase, and TREM-1 activation in neutrophils crucial role in PD, as well as other neurological diseases
mediates apoptosis of dopaminergic neurons. 6 such as stroke and Alzheimer’s disease. The NLRP3
11

Volume 3 Issue 4 (2024) 2 doi: 10.36922/gtm.5082