Cellular Specificity of NF-κB Function in the Nervous System

Dresselhaus, Erica C.; Meffert, Mollie K.

doi:10.3389/fimmu.2019.01043

Cited by 234 publications

(179 citation statements)

References 122 publications

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“…However, no changes were detected in the total hippocampal levels of p65 or in its acetylated form in any animals from the present study (neither in young nor in old ones). However, these results did not rule out a deregulation of NF-κB signaling during aging and after polyphenol exposure, due to its complex regulation and/or cell type specificity (for review see [62,63]). The possible role of RBAP46/48 in the protective effects of polyphenol treatments has been investigated; this is another protein that modulates histone acetylation patterns also associated with the age-related memory loss [34,35].…”

Section: Discussionmentioning

confidence: 95%

Chronic Polyphenon-60 or Catechin Treatments Increase Brain Monoamines Syntheses and Hippocampal SIRT1 LEVELS Improving Cognition in Aged Rats

et al. 2020

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Polyphenolic compounds from green tea have great interest due to its large CONSUMPTION and therapeutic potential on the age-associated brain decline. The current work compares a similar dose regimen of a whole-green-tea extract and catechin in old rats over the course of 36 days. Results showed a significant improvement in visuo-spatial working memory and episodic memory of old rats after polyphenolic compounds administration assessed by behavioral tests. No effects were observed on the age-associated motor coordination decline. Statistically, results were correlated with significant improvements, mainly in hippocampal and striatal noradrenergic and serotonergic systems, but also with the striatal dopaminergic system. Both polyphenolic treatments also reverted the age-associated reduction of the neuroinflammation by modulating protein sirtuin 1 (SIRT1) expression in hippocampus, but no effects were observed in the usual reduction of the histone-binding protein RBAP46/48 protein linked to aging. These results are in line with previous ones obtained with other polyphenolic compounds, suggesting a general protective effect of all these compounds on the age-associated brain decline, pointing to a reduction of the oxidative stress and neuroinflammatory status reduction as the leading mechanisms. Results also reinforce the relevance of SIRT1-mediated mechanism on the neuroprotective effect and rule out the participation of RBAP46/48 protein.

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Section: Discussionmentioning

confidence: 95%

Chronic Polyphenon-60 or Catechin Treatments Increase Brain Monoamines Syntheses and Hippocampal SIRT1 LEVELS Improving Cognition in Aged Rats

et al. 2020

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“…In glial cells, basal NF-κB activity is very low. For this reason, most studies have focused glial NF-κB in models of inflammation, injury, or disease (Dresselhaus and Meffert, 2019) where it is activated in its predominant form, the p50/RelA dimer (Kiebala et al, 2010;Simmons et al, 2016;Gupta et al, 2019). In inflammation, microglia activation results in the transcription of NF-κB-target genes, nitric oxide, IL-1β, and TNFα that in turn induce NF-κB signaling with consequent enhancement of inflammatory mediators that exacerbate neuronal cell death.…”

Section: Nf-κb Factors: Transcriptional Regulators Governing Neuroinfmentioning

confidence: 99%

“…In inflammation, microglia activation results in the transcription of NF-κB-target genes, nitric oxide, IL-1β, and TNFα that in turn induce NF-κB signaling with consequent enhancement of inflammatory mediators that exacerbate neuronal cell death. NF-κB pathway in microglia seems also to actively participate in plasticity mechanisms and neuronal homeostasis in response to injury (Dresselhaus and Meffert, 2019). Likewise, beside inducing pro-inflammatory gene expression, astrocytic NF-κB appears to play a role in the central control of metabolism (Zhang et al, 2017) and, by promoting the clearing of glutamate from the synapses, in the termination of excitatory signals (Ghosh et al, 2011).…”

Section: Nf-κb Factors: Transcriptional Regulators Governing Neuroinfmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

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“…On the other hand in MB_AST, we noticed increased activities in NFκB signaling pathway due to the upregulation of Bcl2 , Csnk2a1 and Chuk in PDm (Figure 2d). Chuk encodes IKKα whose activation is essential for the activation of NFκB canonical pathway by phosphorylating the IκBα protein 44 . Bcl2 and Csnk2a1 has been reported to activate NFκB pathway 45, 46 .…”

Section: Resultsmentioning

confidence: 99%

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

Zhong

Tang

Zhu

et al. 2020

Preprint

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Parkinson's disease (PD) is a neurodegenerative disease leading to the impairment 24 of execution of movement. PD pathogenesis has been largely investigated, but either restricted 25 in bulk level or at certain cell types, which failed to capture cellular heterogeneity and intrinsic 26 interplays among distinct cell types. To overcome this, we applied single-nucleus RNA-seq 27 and single cell ATAC-seq on cerebellum, midbrain and striatum of PD mouse and matched 28 control. With 74,493 cells in total, we comprehensively depicted the dysfunctions under PD 29 pathology covering proteostasis, neuroinflammation, calcium homeostasis and extracellular 30 neurotransmitter homeostasis. Besides, by multi-omics approach, we identified putative 31 biomarkers for early stage of PD, based on the relationships between transcriptomic and 32 epigenetic profiles. We located certain cell types that primarily contribute to PD early 33 pathology, narrowing the gap between genotypes and phenotypes. Taken together, our study 34 provides a valuable resource to dissect the molecular mechanism of PD pathogenesis at single 35 cell level, which could facilitate the development of novel methods regarding diagnosis, 36 monitoring and practical therapies against PD at early stage. 37 38 39 Plenty of studies have made great progress in disentangling the link between -syn 52 oligomerization and neuron death, revealing pathways including proteostasis, mitochondrial 53 dysfunction, neuroinflammation and so on 4 . Nevertheless, the majority of previously studies 54 were conducted at tissue level. Wassouf's team performed RNA-seq on 6-month-old mice 55 overexpressing SNCA ( -syn encoding gene) and found that striatal gene expression profiles 56 3 were greatly disrupted, whose functions were primarily related to neuroinflammation and 57 synaptic plasticity 5 . Richard et. al. combined bulk and single-cell RNA-seq for iPSC-derived 58 dopamine neurons with a GBA mutation and identified HDAC4 as a potential therapeutic PD 59 target 6 . Given the fact that intricate interplay across and within cell types jointly contributes to 60 PD pathogenesis 7 , it is essential to interrogate cell-resolution information in order to unveil the 61 possible PD-related and PD-causing molecular circuits. Single cell sequencing technologies 62 have facilitated the researches in various fields, providing us an opportunity to capture subtler 63 changes that may be masked by bulk sequencing. 64 65Of note, due to synaptic plasticity, 80% of dopaminergic neurons in SN have been lost before 66 any diagnosable symptoms of PD occur 8 . Hence, this raises the necessity to dissect cellular 67 changes in the early stage of PD and identify corresponding markers, ultimately allowing the 68 development of novel early interventions. Nigrostriatal dopamine pathway malfunction 69 attributes largely to PD pathologies 9 . Besides, cerebellum is the pivot of motor coordination 70 but has been often overlooked in Parkinsonism. Therefore, with the aim to explore the 71 deregulation in early sta...

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Cellular Specificity of NF-κB Function in the Nervous System

Cited by 234 publications

References 122 publications

Chronic Polyphenon-60 or Catechin Treatments Increase Brain Monoamines Syntheses and Hippocampal SIRT1 LEVELS Improving Cognition in Aged Rats

Chronic Polyphenon-60 or Catechin Treatments Increase Brain Monoamines Syntheses and Hippocampal SIRT1 LEVELS Improving Cognition in Aged Rats

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Integrated profiling of single cell epigenomic and transcriptomic landscape of Parkinson’s disease mouse brain

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