Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization

Yadikar, Hamad; Torres, Isabel; Aiello, Gabrielle; Kurup, Milin; Yang, Zhihui; Lin, Fan; Kobeissy, Firas; Yost, Richard A.; Wang, Kevin

doi:10.1371/journal.pone.0224952

Cited by 36 publications

(21 citation statements)

References 133 publications

(171 reference statements)

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“…Very recently, in a cell-based model of tauopathies, recapitulating the abnormal deposition of phosphorylated tau protein, characteristic of several neurodegenerative disorders, the CK2 inhibitor TBB was identified as a potential drug candidate for its efficacy against tau hyperphosphorylation and oligomerization processes. 185 …”

Section: Ck2 In Human Diseasesmentioning

confidence: 99%

Protein kinase CK2: a potential therapeutic target for diverse human diseases

Borgo

D’Amore

Sarno

et al. 2021

Sig Transduct Target Ther

217

180

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CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (either viral and host proteins). CK2 is also considered an emerging target for neurological diseases, inflammation and autoimmune disorders, diverse ophthalmic pathologies, diabetes, and obesity. In addition, CK2 activity has been associated with cardiovascular diseases, as cardiac ischemia–reperfusion injury, atherosclerosis, and cardiac hypertrophy. The hypothesis of considering CK2 inhibition for cystic fibrosis therapies has been also entertained for many years. Moreover, psychiatric disorders and syndromes due to CK2 mutations have been recently identified. On these bases, CK2 is emerging as an increasingly attractive target in various fields of human medicine, with the advantage that several very specific and effective inhibitors are already available. Here, we review the literature on CK2 implication in different human pathologies and evaluate its potential as a pharmacological target in the light of the most recent findings.

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Section: Ck2 In Human Diseasesmentioning

confidence: 99%

Protein kinase CK2: a potential therapeutic target for diverse human diseases

Borgo

D’Amore

Sarno

et al. 2021

Sig Transduct Target Ther

217

180

View full text Add to dashboard Cite

show abstract

“…Recent studies supported the potential employment of 1 in tauopathies treatment due to its ability to reduce τ hyperphosphorylation. Yadikar et al evaluated in a tauopathy cell-based model the effect of different PKs inhibitors, including 1, which displayed a substantial reduction of τ phosphorylated in both monomeric (40%) and oligomeric (46-75%) forms [123].…”

Section: Fyn Inhibitionmentioning

confidence: 99%

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Demuro

Martino

Ortega

et al. 2021

IJMS

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Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.

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“…The counterstaining with phalloidin reveals in multichannel immunofluorescent merged images of tau positioning along phalloidin-revealed threads, presumably microtubules. Based on this finding, the prospective aim was to use tau in two types of studies: (a) to test comparatively the functional state of its epitopes in monomer tau of DPSCs and in NFTs of the AD brain samples and (b) to test the propensity of the protein sites in which these epitopes are located to undergo initial steps of aggregation toward NFTs under the influence of currently known in vitro inducers of tau phosphorylation aggregation to model the formation of NFT, such as okadaic acid ( 79 , 80 ) and inhibitors of these processes as drug candidates against neurodegeneration ( 81 ). In this study, we describe the results of the first study hypothesizing that the active or inactive state of epitopes (evaluated by the binding/nonbinding of the respective antibody) in monomer tau of DPSCs and in its aggregated NFT form in samples from AD brains would provide information about the mode of the participation of respective tau sites in neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Human Dental Pulp Stem Cells Display a Potential for Modeling Alzheimer Disease-Related Tau Modifications

et al. 2021

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We present here the first description of tau in human dental pulp stem cells (DPSCs) evidenced by RT-PCR data on expression of the gene MAPT and by immunocytochemical detection of epitopes by 12 anti-tau antibodies. The tau specificity of eight of these antibodies was confirmed by their affinity to neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) postmortem brain samples. We therefore used DPSCs and AD brain samples as a test system for determining the probability of the involvement of tau epitopes in the mechanisms converting tau into NFT in AD. Three antibodies to non-phosphorylated and seven antibodies to phosphorylated epitopes bound tau in both DPSCs and AD NFTs, thus suggesting that their function was not influenced by inducers of formation of NFTs in the AD brain. In contrast, AT100, which recognizes a hyperphosphorylated epitope, did not detect it in the cytoplasm of DPSCs but detected it in AD brain NFTs, demonstrating its AD diagnostic potential. This indicated that the phosphorylation/conformational events required for the creation of this epitope do not occur in normal cytoplasm and are a part of the mechanism (s) leading to NFT in AD brain. TG3 bound tau in the cytoplasm and in mitotic chromosomes but did not find it in nuclei. Collectively, these observations characterize DPSCs as a novel tau-harboring neuronal lineage long-term propagable in vitro cellular system for the normal conformational state of tau sites, detectable by antibodies, with their state in AD NFTs revealing those involved in the pathological processes converting tau into NFTs in the course of AD. With this information, one can model the interaction of tau with inducers and inhibitors of hyperphosphorylation toward NFT-like aggregates to search for drug candidates. Additionally, the clonogenicity of DPSCs provides the option for generation of cell lineages with CRISPR-mutagenized genes of familial AD modeling.

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Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization

Cited by 36 publications

References 133 publications

Protein kinase CK2: a potential therapeutic target for diverse human diseases

Protein kinase CK2: a potential therapeutic target for diverse human diseases

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Human Dental Pulp Stem Cells Display a Potential for Modeling Alzheimer Disease-Related Tau Modifications

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