Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in Motor Neuron-Like Cells

Hicks, David; Cross, Laura L.; Williamson, Ritchie; Rattray, Marcus

doi:10.1007/s11064-019-02832-2

Cited by 25 publications

(22 citation statements)

References 77 publications

(103 reference statements)

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“…CK-1 was the first kinase identified to phosphorylate TDP-43 in vivo in more than 29 different sites, being 18 of them located in the C-terminal glycine-rich region 7 . Moreover, different stress signaling cause CK-1-dependent phosphorylation of TDP-43 triggering its cytosolic mislocalization and accumulation 8,9 . Furthermore, TDP-43 binds directly to and regulates the expression of CK-1ε mRNA 10 .…”

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confidence: 99%

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Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Martínez-González

Rodríguez‐Cueto

Cabezudo

et al. 2020

Sci Rep

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Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.

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confidence: 99%

“…However, its dysregulation leads to different pathologies including cancer and neurodegenerative diseases 11 . Recently, inhibition of CK-1, mainly the δ and ε isoforms, has been proposed as a potential treatment for different neurodegenerative diseases including ALS, FTD 9 and Alzheimer's disease 12 .…”

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confidence: 99%

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Martínez-González

Rodríguez‐Cueto

Cabezudo

et al. 2020

Sci Rep

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“…They reduced levels of nuclear TDP-43, decreased neuronal loss, and reversed cognitive and motor decline (Wenqiang et al, 2014). In subsequent studies, these TKIs could reverse the effects of TDP-43 on synaptic proteins, increase astrocytic function, and restore glutamate and neurotransmitter balance in TDP-43 transgenic mice that overexpressed the full length protein in neurons (Heyburn et al, 2016). Finally, in a recent high-throughput screening approach, bosutinib was found effective in iPSC-derived ALS patient cells (Imamura et al, 2017).…”

Section: F I G U R Ementioning

confidence: 98%

“…Notably, these inclusions did not occur following exposure to staurosporine as previously described in other systems (see above) or with trans‐4‐carboxy‐ l ‐proline (PDC). Recently, it has been reported that tunicamycin can induce CK1 expression in mature NSC‐34 cells that phosphorylates TDP‐43 and induces its translocation to the cytoplasm (Hicks, Cross, Williamson, & Rattray, 2020).…”

Section: Tdp‐43 Aggregate Formationmentioning

confidence: 99%

Targeting TDP‐43 proteinopathy with drugs and drug‐like small molecules

Buratti

2020

British J Pharmacology

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Following the discovery of the involvement of the ribonucleoprotein TDP‐43 in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), a major research focus has been to develop treatments that can prevent or alleviate these disease conditions. One pharmacological approach has been to use TDP‐43‐based disease models to test small molecules and drugs already known to have some therapeutic effect in a variety of neurodegenerative conditions. In parallel, various disease models have been used to perform high‐throughput screens of drugs and small compound libraries. The aim of this review will be to provide a general overview of the compounds that have been described to alter pathological characteristics of TDP‐43. These include expression levels, cytoplasmic mis‐localization, post‐translational modifications, cleavage, stress granule recruitment and aggregation. In parallel, this review will also address the use of compounds that modify the autophagic/proteasome systems that are known to target TDP‐43 misfolding and aggregation. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

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“…Researches showed that the decreased AQPs protein levels were correlated with ER stress [21]. Excessive ER stress could result in tissue damage and cell injury, and it has been observed in many inflammatory diseases, including asthma [22,23]. Recent studies indicate that ER stress might be a potential target for controlling inflammatory responses [24].…”

Section: Introductionmentioning

confidence: 99%

Sevoflurane modulates AQPs (1,5) expression and endoplasmic reticulum stress in mice lung with allergic airway inflammation

et al. 2019

Bioscience Reports

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Sevoflurane was found to show protective roles in mice with asthma, however, the mechanism of which needs further exploring. Aquaporins (AQPs) have been demonstrated to be involved in the pathogenesis of asthma, while endoplasmic reticulum stress has been reported to be related to many inflammatory diseases and involved in protein processing, including AQPs. The present study aimed to determine the role of sevoflurane in AQPs (AQP1,3,4,5) expression in mice with allergic airway inflammation and the probable mechanism. The increased number of inflammatory cells infiltrating the lung tissue, and the elevated levels of tumor necrosis factor-α (TNF-α) and interleukin (IL) 13 (IL-13) were all decreased after sevoflurane treatment (all P<0.05). Meanwhile, mRNA levels of AQP1 and AQP5 but not AQP3 and AQP4 were decreased in ovalbumin (OVA)-induced allergic mice lung. Both the decreased mRNA expression and protein levels of AQP1 and AQP5 in allergic lung tissues were reversed by sevoflurane treatment. Furthermore, we established that sevoflurane inhibited the OVA-induced protein increase in the endoplasmic reticulum (ER) stress markers BiP and C/EBP homologous protein (CHOP). Collectively, these findings suggested that sevoflurane modulated the expression and protein level of AOPs (AQP1, AQP5) as well as inhibited ER stress response in OVA-induced allergic airway inflammation of mice.

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Endoplasmic Reticulum Stress Signalling Induces Casein Kinase 1-Dependent Formation of Cytosolic TDP-43 Inclusions in Motor Neuron-Like Cells

Cited by 25 publications

References 77 publications

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment

Targeting TDP‐43 proteinopathy with drugs and drug‐like small molecules

Sevoflurane modulates AQPs (1,5) expression and endoplasmic reticulum stress in mice lung with allergic airway inflammation

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