Inflammatory Mechanisms in Parkinson’s Disease: From Pathogenesis to Targeted Therapies

Lee, Stellina Y H; Yates, Nathanael J.; Tye, Susannah J.

doi:10.1177/1073858421992265

Cited by 21 publications

(11 citation statements)

References 188 publications

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“…Progressive loss of midbrain dopaminergic neurons in the substantia nigra and axonal terminals in the striatum gives rise to characteristic motor disturbances [ 24 ]. Although the underlying mechanisms are still unknown, increasing studies report neuroinflammation as a crucial factor in the pathogenesis of PD, evidencing that inflammatory factors are closely related to the dopaminergic neuron loss in PD [ 25 , 26 ]. For this reason, targeting neuroinflammation may provide neuroprotection in PD.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson’s Disease

Nuccio

Cianciulli

Porro

et al. 2021

Biology

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Vitamin C (Vit C) is anutrient present in many foods, particularly citrus fruits, green vegetables, tomatoes, and potatoes. Vit C is studied for its applications in the prevention and management of different pathologies, including neurodegenerative diseases. Neuroinflammation is a defense mechanism activated by a stimulus or an insult that is aimed at the preservation of the brain by promoting tissue repair and removing cellular debris; however, persistent inflammatory responses are detrimental and may lead to the pathogenesis and progression of neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease. PD is one of the most common chronic progressive neurodegenerative disorders, and oxidative stress is one of the most important factors involved in its pathogenesis and progression.Due to this, research on antioxidant and anti-inflammatory compounds is an important target for counteracting neurodegenerative diseases, including PD. In the central nervous system, the presence of Vit C in the brain is higher than in other body districts, but why and how this occurs is still unknown. In this research, Vit C, with its anti-inflammatory and anti-oxidative properties, is studied to better understand its contribution to brain protection; in particular, we have investigated the neuroprotective effects of Vit C in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD and its role in the modulation of neuroinflammation. First, we observed that Vit C significantly decreased the MPTP-induced loss of tyrosine hydroxylase (TH)-positive dopaminergic neuronal cells in the substantia nigra, as well as microglial cell activation and astrogliosis. Furthermore, gait and spontaneous locomotor activity, evaluated by an automated treadmill and the Open Field test, respectively, were partially ameliorated by Vit C treatment in MPTP-intoxicated animals. In relation to neuroinflammation, results show that Vit C reduced the protein and mRNA expression of inflammatory cytokines such as IL-6, TLR4, TNF-α, iNOS, and CD40, while anti-inflammatory proteins such as IL-10, CD163, TGF-β, and IL-4 increased. Interestingly, we show for the first time that Vit C reduces neuroinflammation by modulating microglial polarization and astrocyte activation. Moreover, Vit C was able to reduce NLRP3 activation, which is linked to the pathogenesis of many inflammatory diseases, including neuroinflammatory disorders. In conclusion, our study provides evidence that Vit C may represent a new promising dietary supplement for the prevention and alleviation of the inflammatory cascade of PD, thus contributing to neuroprotection.

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Section: Discussionmentioning

confidence: 99%

Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson’s Disease

Nuccio

Cianciulli

Porro

et al. 2021

Biology

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“…Studies of TAGLN3 have not been reported in patients with PD or T2D. The pathogeneses of PD and T2D both involve inflammatory processes [46,47]. NF-κB plays a major role in the etiology of neurodegenerative disease and T2D [48].…”

Section: Discussionmentioning

confidence: 99%

Identification of Shared Pathogenetic Genes in Parkinson’s Disease and Type 2 Diabetes

Chen

Wang

et al. 2023

Preprint

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Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Increasing evidence suggests that PD patients have alterations in glucose metabolism and that type 2 diabetes (T2D) is a risk factor for PD. Although extensive literature has shown that there is a close linkage between PD and T2D, the molecular and genetic mechanisms of these two diseases are still unclear. Object: The aim of this study was to explore the shared pathogenetic genes in PD and T2D. Method: We downloaded microarray data for PD and T2D from the Gene Expression Omnibus (GEO) database. The RNA microarray data of human postmortem substantia nigra samples were accessed from the GSE49036, GSE20141 and GSE7621 datasets. The RNA microarray data of human pancreatic islet samples were from the GSE76896 dataset. The differentially expressed genes between the PD/control and T2D/control groups were analyzed. Gene coexpression modules related to PD and T2D were constructed by weighted gene coexpression network analysis (WGCNA). Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on the common genes between the PD and T2D key modules. Finally, through protein‒protein interaction (PPI) network analysis, four shared pathogenetic genes were identified. Result: There were 348 downregulated differentially expressed genes and 221 upregulated differentially expressed genes between PD patients and healthy controls. There were 218 downregulated differentially expressed genes and 65 upregulated differentially expressed genes between T2D patients and healthy controls. Thirty-six common differentially expressed genes with consistent fold change directions were obtained from the overlapping differentially expressed genes between the PD and T2D datasets. In the PD datasets, the turquoise module was the key module related to the pathogenesis of PD and included 3735 genes. In the T2D dataset, the turquoise module was the most significant module related to the pathogenesis of T2D and included 790 genes. The common genes between the PD and T2D key modules were primarily enriched in synaptic transmission and insulin signaling. After the construction of the PPI network, we identified four shared pathogenetic genes, namely, TAGLN3, STMN2, SYT4 and GAP43. Conclusion: In conclusion, TAGLN3, STMN2, SYT4 and GAP43 were the shared pathogenetic genes of PD and T2D, which might provide new therapeutic targets for PD and T2D.

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“…One possible reason is the inconsistency in inclusion criteria: they included data from all types of machines, while we only included data acquired from Siemens' machines; Another possible reason is the inconsistency in analysis methods: they combined deformation-based morphometry and independent component analysis, focusing more on network structure, while we used surface-based morphometry and voxel-based morphometry methods, focusing more on brain region structures. Some researchers believe that "compensated hyperplasia" appears in specific brain regions in early PD, which might be related to the compensatory neuroinflammatory response 30,31 . Astrocytes are activated by proinflammatory cytokines, resulting in cell hypertrophy, astrocyte proliferation, protrusion extension, and interlacing, which leads to increasing surface area and/or thickness of the cortex 32 .…”

Section: Discussionmentioning

confidence: 99%

Baseline cerebral structural morphology predict freezing of gait in early drug-naïve Parkinson’s disease

Huang

Ruan

et al. 2022

npj Parkinsons Dis.

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Freezing of gait (FOG) greatly impacts the daily life of patients with Parkinson’s disease (PD). However, predictors of FOG in early PD are limited. Moreover, recent neuroimaging evidence of cerebral morphological alterations in PD is heterogeneous. We aimed to develop a model that could predict the occurrence of FOG using machine learning, collaborating with clinical, laboratory, and cerebral structural imaging information of early drug-naïve PD and investigate alterations in cerebral morphology in early PD. Data from 73 healthy controls (HCs) and 158 early drug-naïve PD patients at baseline were obtained from the Parkinson’s Progression Markers Initiative cohort. The CIVET pipeline was used to generate structural morphological features with T1-weighted imaging (T1WI). Five machine learning algorithms were calculated to assess the predictive performance of future FOG in early PD during a 5-year follow-up period. We found that models trained with structural morphological features showed fair to good performance (accuracy range, 0.67–0.73). Performance improved when clinical and laboratory data was added (accuracy range, 0.71–0.78). For machine learning algorithms, elastic net-support vector machine models (accuracy range, 0.69–0.78) performed the best. The main features used to predict FOG based on elastic net-support vector machine models were the structural morphological features that were mainly distributed in the left cerebrum. Moreover, the bilateral olfactory cortex (OLF) showed a significantly higher surface area in PD patients than in HCs. Overall, we found that T1WI morphometric markers helped predict future FOG occurrence in patients with early drug-naïve PD at the individual level. The OLF exhibits predominantly cortical expansion in early PD.

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Inflammatory Mechanisms in Parkinson’s Disease: From Pathogenesis to Targeted Therapies

Cited by 21 publications

References 188 publications

Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson’s Disease

Inflammatory Response Modulation by Vitamin C in an MPTP Mouse Model of Parkinson’s Disease

Identification of Shared Pathogenetic Genes in Parkinson’s Disease and Type 2 Diabetes

Baseline cerebral structural morphology predict freezing of gait in early drug-naïve Parkinson’s disease

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