Functions of p38 MAP Kinases in the Central Nervous System

Asih, Prita R.; Prikas, Emmanuel; Stefanoska, Kristie; Tan, Amanda R. P.; Ahel, Holly I.; Ittner, Arne

doi:10.3389/fnmol.2020.570586

Cited by 103 publications

(84 citation statements)

References 333 publications

(520 reference statements)

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“…Known substrates are indicated, but targets involved in p38α-regulated synaptic plasticity, myelination or neuroinflammation remain largely unknown. There is also evidence that the role of p38α in myelination may depend on both the cause of nerve injury and the cell type 252 . d | In hepatocytes, p38α can promote cell death or support cell viability depending on the strength of the stress: high levels of stress (such as combination of a high-fat diet (HFD) with infection/inflammation) results in cell death, whereas milder stress (such as HFD alone) generally promotes hepatocyte function in metabolizing fatty acids, by increasing their trafficking and β-oxidation, thereby reducing triglyceride (TG) storage and load in the liver.…”

Section: P38α Substrates and Functionsmentioning

confidence: 99%

Diversity and versatility of p38 kinase signalling in health and disease

Cánovas

Nebreda

2021

Nat Rev Mol Cell Biol

327

275

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Section: P38α Substrates and Functionsmentioning

confidence: 99%

Diversity and versatility of p38 kinase signalling in health and disease

Cánovas

Nebreda

2021

Nat Rev Mol Cell Biol

327

275

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“…Instead, they may be caused by the dysregulation of signaling kinases, which will affect their downstream substrates. We found increased phosphorylation of RPS6KA3 and MAPK14 in DMSXL astrocytes by mass spectrometry, which has been shown to induce kinase activity (Romeo et al, 2012;Asih et al, 2020). The possible contribution of RPS6KA3 and MAPK14 to global changes in the phosphoproteome requires further studies.…”

Section: Discussionmentioning

confidence: 77%

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

González-Barriga

Lallemant

Dincã

et al. 2021

Front. Cell. Neurosci.

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Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system (CNS) has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.

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“…After identifying the involvement of LPS-linked AKT signaling in the effects of sorafenib in microglia, we next investigated whether sorafenib modulates P38 signaling, a key pathway in the production of inflammatory mediators (51). For instance, activation of p-P38 T180/Y182 by Ras-Raf kinases stimulates the release of proinflammatory cytokines from microglia (52,53), and the VEGFRs inhibitor nintedanib decreases p-P38 immunoreactivity in GC7901 and MKN45 cells (54). Cotreatment of non-small cell lung carcinoma (NSCLC) cells with VEGF and vandetanib or axitinib, both VEGFR inhibitors, significantly suppresses the phosphorylation of P38 in a dosedependent manner (55).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice

Kim

Park

et al. 2021

Front. Immunol.

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Sorafenib is FDA-approved for the treatment of primary kidney or liver cancer, but its ability to inhibit many types of kinases suggests it may have potential for treating other diseases. Here, the effects of sorafenib on neuroinflammatory responses in vitro and in vivo and the underlying mechanisms were assessed. Sorafenib reduced the induction of mRNA levels of the proinflammatory cytokines COX-2 and IL-1β by LPS in BV2 microglial cells, but in primary astrocytes, only COX-2 mRNA levels were altered by sorafenib. Interestingly, sorafenib altered the LPS-mediated neuroinflammatory response in BV2 microglial cells by modulating AKT/P38-linked STAT3/NF-kB signaling pathways. In LPS-stimulated wild-type mice, sorafenib administration suppressed microglial/astroglial kinetics and morphological changes and COX-2 mRNA levels by decreasing AKT phosphorylation in the brain. In 5xFAD mice (an Alzheimer’s disease model), sorafenib treatment daily for 3 days significantly reduced astrogliosis but not microgliosis. Thus, sorafenib may have therapeutic potential for suppressing neuroinflammatory responses in the brain.

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Functions of p38 MAP Kinases in the Central Nervous System

Cited by 103 publications

References 333 publications

Diversity and versatility of p38 kinase signalling in health and disease

Diversity and versatility of p38 kinase signalling in health and disease

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice

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