Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes

Lee, Chingli; Low, Clara Ying Bei; Wong, Siew Heng; Lai, Mitchell K.P.; Tan, Michelle

doi:10.1038/srep43651

Cited by 18 publications

(18 citation statements)

References 41 publications

(52 reference statements)

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“…Mutations in key astrocyte genes have been associated with neurodegenerative disease. Mutations of Fyn tyrosine kinase are associated with increased inflammatory responses in Alzheimer’s disease ( Lee et al, 2016 , 2017 ). Mutations in the gene encoding TGF-β have been associated with AD risk ( Caraci et al, 2012 , 2018 ).…”

Section: Astrocytesmentioning

confidence: 99%

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

O’Carroll

Cook

Young

2021

Front. Mol. Neurosci.

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Different glial cell types are found throughout the central (CNS) and peripheral nervous system (PNS), where they have important functions. These cell types are also involved in nervous system pathology, playing roles in neurodegenerative disease and following trauma in the brain and spinal cord (astrocytes, microglia, oligodendrocytes), nerve degeneration and development of pain in peripheral nerves (Schwann cells, satellite cells), retinal diseases (Müller glia) and gut dysbiosis (enteric glia). These cell type have all been proposed as potential targets for treating these conditions. One approach to target these cell types is the use of gene therapy to modify gene expression. Adeno-associated virus (AAV) vectors have been shown to be safe and effective in targeting cells in the nervous system and have been used in a number of clinical trials. To date, a number of studies have tested the use of different AAV serotypes and cell-specific promoters to increase glial cell tropism and expression. However, true glial-cell specific targeting for a particular glial cell type remains elusive. This review provides an overview of research into developing glial specific gene therapy and discusses some of the issues that still need to be addressed to make glial cell gene therapy a clinical reality.

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Section: Astrocytesmentioning

confidence: 99%

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

O’Carroll

Cook

Young

2021

Front. Mol. Neurosci.

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“…Reactive astrocytes fail to uptake glutamate and K + clearance leading to increased epileptiform discharge (Devinsky et al, 2013 ). Upregulation of Fyn mRNA is attributable to astrocyte activation in the KA-induced epilepsy mouse model (Chun et al, 2004 ) and in lipopolysaccharide (LPS)-stimulated primary neuronal cultures (Lee et al, 2017 ). Tau phosphorylation also increased reactive astrocytes expression (Forman et al, 2005 ; Liu et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

Putra

Puttachary

Liu

et al. 2020

Front. Cell. Neurosci.

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Both Fyn and tau have been associated with neuronal hyperexcitability and neurotoxicity in many tauopathies, including Alzheimer's disease (AD). Individual genetic ablation of fyn or tau appears to be protective against aberrant excitatory neuronal activities in AD and epilepsy models. It is, however, still unknown whether ablation of both Fyn and tau can likely elicit more profound anti-seizure and neuroprotective effects. Here, we show the effects of genetic deletion of Fyn and/or tau on seizure severity in response to pentylenetetrazole (PTZ)-induced seizure in mouse models and neurobiological changes 24 h post-seizures. We used Fyn KO (fyn−/−), tau KO (tau−/−), double knockout (DKO) (fyn−/−/tau−/−), and wild-type (WT) mice of the same genetic background. Both tau KO and DKO showed a significant increase in latency to convulsive seizures and significantly decreased the severity of seizures post-PTZ. Although Fyn KO did not differ significantly from WT, in response to PTZ, Fyn KO still had 36 ± 8% seizure reduction and a 30% increase in seizure latency compared to WT. Surprisingly, in contrast to WT, Fyn KO mice showed higher mortality in <20 min of seizure induction; these mice had severe hydrocephalous. None of the tau−/− and DKO died during the study. In response to PTZ, all KO groups showed a significant reduction in neurodegeneration and gliosis, in contrast to WT, which showed increased neurodegeneration [especially, parvalbumin (PV)-GABAergic interneurons] and gliosis. DKO mice had the most reduced gliosis. Immunohistochemically, phospho-tau (AT8, pS199/S202), Fyn expression, as well as Fyn-tau interaction as measured by PLA increased in WT post-PTZ. Moreover, hippocampal Western blots revealed increased levels of AT8, tyrosine phospho-tau (pY18), and phosphorylated Src tyrosine family kinases (pSFK) in PTZ-treated WT, but not in KO, compared to respective controls. Furthermore, PV interneurons were protected from PTZ-induced seizure effects in all KO mice. The levels of inwardly rectifying potassium (Kir 4.1) channels were also downregulated in astrocytes in the WT post-PTZ, while its levels did not change in KO groups. Overall, our results demonstrated the role of Fyn and tau in seizures and their impact on the mediators of early epileptogenesis in PTZ model.

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“…Constitutively active FynT (Y528F), an alternative splicing form in hematopoietic cells, induced highly increased pro-inflammatory cytokines and chemokines after prolonged TNFα treatment. However, these effects were abolished by broad Src-family kinase inhibitor PP2 and siRNA against FynT [ 68 ]. In addition, Fyn activity was critical for the initiation and progression of inflammatory signaling in adipose tissue [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation

Jeong

Shin

Lee

et al. 2020

IJMS

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Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that caffeoyl-prolyl-histidine amide (CA-PH), which is CA conjugated with proline-histidine dipeptide, relieves atopic dermatitis (AD)-like phenotypes in mouse. In this study, we investigated the molecular mechanism underlying CA-PH-mediated alleviation of AD-like phenotypes using cell line and AD mouse models. We confirmed that CA-PH suppresses AD-like phenotypes, such as increased epidermal thickening, infiltration of mast cells, and dysregulated gene expression of cytokines. CA-PH suppressed up-regulation of cytokine expression through inhibition of nuclear translocation of NF-κB. Using a CA-PH affinity pull-down assay, we found that CA-PH binds to Fyn. In silico molecular docking and enzyme kinetic studies revealed that CA-PH binds to the ATP binding site and inhibits Fyn competitively with ATP. CA-PH further suppressed spleen tyrosine kinase (SYK)/inhibitor of nuclear factor kappa B kinase (IKK)/inhibitor of nuclear factor kappa B (IκB) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In addition, chronic application of CA-PH, in contrast with that of glucocorticoids, did not induce up-regulation of regulated in development and DNA damage response 1 (REDD1), reduction of mammalian target of rapamycin (mTOR) signaling, or skin atrophy. Thus, our study suggests that CA-PH treatment may help to reduce skin inflammation via down-regulation of NF-κB activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.

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Selective induction of alternatively spliced FynT isoform by TNF facilitates persistent inflammatory responses in astrocytes

Cited by 18 publications

References 41 publications

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation

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