Significant roles of neuroinflammation in Parkinson’s disease: therapeutic targets for PD prevention

Lee, Yujeong; Lee, Seulah; Chang, Seung‐Cheol; Lee, Jaewon

doi:10.1007/s12272-019-01133-0

Cited by 124 publications

(87 citation statements)

References 107 publications

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“…Accumulating evidence supports dysregulated glia-related mechanisms in neuroinflammatory disorders, including PD [88,89]. However, the critical contribution of potential inflammatory mediators in mediating neurodegeneration in the context of PD remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

Samidurai

Tarale

Janarthanam

et al. 2020

Cells

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Astrocytic dysfunction has been implicated in Parkinson’s disease (PD) pathogenesis. While the Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 signaling axis is known to play a role in PD-like neuropathology, the molecular mechanisms that govern this process remain poorly understood. Herein, we show that TWEAK levels are elevated in PD serum compared to controls. Moreover, using both U373 human astrocyte cells and primary mouse astrocytes, we demonstrate that TWEAK induces mitochondrial oxidative stress as well as protein kinase C delta (PKCδ) and signal transducer and activator of transcription 3 (STAT3) activation, accompanied by NLRC4 inflammasome activation and upregulation and release of proinflammatory cytokines, including IL-1β, TNF-α, and IL-18. Mechanistically, TWEAK-induced PKCδ activation enhances the STAT3/NLRC4 signaling pathway and other proinflammatory mediators through a mitochondrial oxidative stress-dependent mechanism. We further show that PKCδ knockdown and mito-apocynin, a mitochondrial antioxidant, suppress TWEAK-induced proinflammatory NLRC4/STAT3 signaling and cellular oxidative stress response. Notably, we validated our in vitro findings in an MPTP mouse model of PD and in mice receiving intrastriatal administration of TWEAK. These results indicate that TWEAK is a key regulator of astroglial reactivity and illustrate a novel mechanism by which mitochondrial oxidative stress may influence dopaminergic neuronal survival in PD.

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Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

Samidurai

Tarale

Janarthanam

et al. 2020

Cells

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“…Mutations in microtubule associated proteins that lead to hyperphosphorylation and aggregation of tau in brain are linked to a family of neurodegenerative disorders, tauopathies, which leads to destabilization of tau-microtubule interactions leading to instability, axon transport defects, mitochondrial dysfunction, neuroinflammation, and ultimately neuronal death. Mitochondrial dysfunction is a major source of ROS, though more recently microglial cells have also been identified as ROS generators in tauopathies and other neurodegenerative diseases such as PD [41].…”

Section: Mitochondria Dysfunction and Neuroinflammationmentioning

confidence: 99%

“…DNAJC15 forms a stable subcomplex with a component of the mitochondrial import motor and so participates in the import of proteins into mitochondria, and thus assists in the regulation of the mitochondrial respiratory chain. As a member of the family of J proteins, it also participates, in conjunction with Hsp70 chaperone proteins, in cellular processes, such as folding of proteins, prevention of protein aggregation, disaggregation of proteins and protein transport [40][41][42]. PEX19 acts as key component of peroxisomes [77] by acting as a chaperone for insertion of peroxisomal membrane proteins (PMPs).…”

Section: Ubiquitin Proteasome System (Ups) Dysfunctionmentioning

confidence: 99%

Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson’s disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity

Corley

Ross

et al. 2020

BMC Neurosci

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Background: Parkinson's disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person's risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. Results: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K Bead-Chip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n = 20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (p < 0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGCs, identified 8 and 18 DML in brain and blood DNA, respectively (p < 0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases. Conclusions: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

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“…The pathological mechanism of PD is not clear until now. Existing studies have shown that PD may be closely related to oxidative stress, glutamate receptor abnormality, ubiquitin-protease dysfunction, inflammation and cytokine activation, neurotrophic factor dysfunction, mitochondrial damage, cytoskeleton abnormality, synaptic dysfunction, and apoptotic pathway activation [13][14][15][16][17]. In this study, we found the dynamic changes of genes associated with pathways of the neurotropic signaling pathway, ECM-receptor interaction, oxidative phosphorylation, apoptosis, necroptosis, dopaminergic synapse, Parkinson's disease, and other KEGG pathways, during the MPTP/p-induced progressive PD mice.…”

Section: Discussionmentioning

confidence: 99%

“…Nowadays, the pathological mechanism of PD is not clear. Existing studies have shown that PD may be closely related to oxidative stress, glutamate receptor abnormality, ubiquitin-protease dysfunction, inflammation and cytokine activation, neurotrophic factor dysfunction, mitochondrial damage, cytoskeleton abnormality, synaptic dysfunction, and apoptotic pathway activation [13][14][15][16][17]. In addition, the pathogenesis of PD may change at different cellular levels, especially at transcriptional level [18].…”

Section: Introductionmentioning

confidence: 99%

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

et al. 2020

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Parkinson’s disease (PD) is a neurodegenerative disease caused by a variety of unclear complex pathogenic factors. The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced progressive PD mice is a well-recognized classic model for studying PD, but the molecular toxicology of this model is still unclear. Here, for the first time, we report gradual neurodegenerative processes in MPTP/p-induced progressive PD mice model using RNA-seq. Transcriptional responses are orchestrated to regulate the expression of many genes in substantia nigra, such as Ntf3, Pitx3, Th, and Drd2, leading to the degeneration of dopaminergic neurons at last. We proposed that the established model could be divided into three phases based on their molecular toxicological features: “the stress response phase” which maintained the microenvironment homeostasis, “the pre-neurodegenerative phase” which demonstrated observed MPTP/p cytotoxicity and gradual degeneration of dopaminergic neurons, and “the neurodegenerative phase” which reflected distinct damage and dopaminergic neuron apoptotic process. Glia cells exhibited a certain protective effect on dopaminergic neurons in 3rd and 6th MPTP/p-induced cytotoxicity. But in 10th MPTP/p injection, glia cells play a promoting role in PD and tissue damages caused by oxidative stress. This study also indicated that the substantia nigra of PD mice showed unique patterns of changes at each stage. Moreover, neurotrophic signaling pathway, ECM-receptor interaction, oxidative phosphorylation, apoptosis and necroptosis were enriched at 3rd and 6th MPTP/p injection, which might be associated with the PD progress. This study provided an extensive data set of molecular toxicology for elucidating of PD progression and offered comprehensive theoretical knowledge for the development of new therapy.

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Significant roles of neuroinflammation in Parkinson’s disease: therapeutic targets for PD prevention

Cited by 124 publications

References 107 publications

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) Enhances Activation of STAT3/NLRC4 Inflammasome Signaling Axis through PKCδ in Astrocytes: Implications for Parkinson’s Disease

Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson’s disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity

Molecular Regulatory Mechanism and Toxicology of Neurodegenerative Processes in MPTP/Probenecid-Induced Progressive Parkinson’s Disease Mice Model Revealed by Transcriptome

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