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Down syndrome is the most common chromosomal abnormality in humans. Patients with Down syndrome have hematologic disorders, including mild to moderate thrombocytopenia. In case of Down syndrome, thrombocytopenia is not associated with bleeding, and it remains poorly characterized regarding molecular mechanisms. We investigated the effects of overexpression of Dyrk1A, an important factor contributing to some major Down syndrome phenotypes, on platelet number and bleeding in mice. Mice overexpressing Dyrk1A have a decrease in platelet number by 20%. However, bleeding time was found to be reduced by 50%. The thrombocytopenia and the decreased bleeding time observed were not associated to an abnormal platelet receptors expression, to a defect of platelet activation by ADP, thrombin or convulxin, to the presence of activated platelets in the circulation or to an abnormal half‐life of the platelets. To propose molecular mechanisms explaining this discrepancy, we performed a network analysis of Dyrk1A interactome and demonstrated that Dyrk1A, fibronectin and fibrinogen interact indirectly through two distinct clusters of proteins. Moreover, in mice overexpressing Dyrk1A, increased plasma fibronectin and fibrinogen levels were found, linked to an increase of the hepatic fibrinogen production. Our results indicate that overexpression of Dyrk1A in mice induces decreased bleeding consistent with increased plasma fibronectin and fibrinogen levels, revealing a new role of Dyrk1A depending on its indirect interaction with these two proteins. [ABSTRACT FROM AUTHOR]

Background: Sebaceous glands (SGs) synthesize and secret sebum to protect and moisturize the dermal system via the complicated endocrine modulation. Dysfunction of SG are usually implicated in a number of dermal and inflammatory diseases. However, the molecular mechanism behind the differentiation, development and proliferation of SGs is far away to fully understand. Methods: Herein, the rat volar and mammary tissues with abundant SGs from female SD rats with (post-natal day (PND)-35) and without puberty onset (PND-25) were arrested, and conducted RNA sequencing. The protein complex of Neuropeptide Y receptor Y2 (NPY2R)/NPY5R/Nuclear factor of activated T cells 1 (NFATc1) was performed by immunoprecipitation, mass spectrum and gel filtration. Genome-wide occupancy of NFATc1 was measured by chromatin immunoprecipitation sequencing. Target proteins' expression and localization was detected by western blot and immunofluorescence. Results: NPY2R gene was significantly up-regulated in volar and mammary SGs of PND-25. A special protein complex of NPY2R/NPY5R/NFATc1 in PND-25. NFATc1 was dephosphorylated and activated, then localized into nucleus to exert as a transcription factor in volar SGs of PND-35. NFATc1 was especially binding at enhancer regions to facilitate the distal SG and sebum related genes' transcription. Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) contributed to NFATc1 phosphorylation in PND-25, and inactivated of DYRK1A resulted in NFATc1 dephosphorylation and nuclear localization in PND-35. Conclusions: Our findings unmask the new role of NPY2R/NFATc1/DYRK1A in pubertal SG, and are of benefit to advanced understanding the molecular mechanism of SGs' function after puberty, and provide some theoretical basis for the treatment of acne vulgaris from the perspective of hormone regulation. [ABSTRACT FROM AUTHOR]

Introduction: Lomerizine is a calcium channel blocker that crosses the blood-brain barrier and is used clinically in the treatment of migraines. However, whether lomerizine is beneficial in modulating neuroinflammatory responses has not been tested yet. Methods: To assess the potential of lomerizine for repurposing as a treatment for neuroinflammation, we investigated the effects of lomerizine on LPS-induced proinflammatory responses in BV2 microglial cells, Alzheimer's disease (AD) excitatory neurons differentiated from induced pluripotent stem cells (iPSCs), and in LPS-treated wild type mice. Results: In BV2 microglial cells, lomerizine pretreatment significantly reduced LPSevoked proinflammatory cytokine and NLRP3 mRNA levels. Similarly, lomerizine pretreatment significantly suppressed the increases in Iba-1, GFAP, proinflammatory cytokine and NLRP3 expression induced by LPS in wild-type mice. In addition, lomerizine posttreatment significantly decreased LPS-stimulated proinflammatory cytokine and SOD2 mRNA levels in BV2 microglial cells and/or wild-type mice. In LPS-treated wild-type mice and AD excitatory neurons differentiated from iPSCs, lomerizine pretreatment ameliorated tau hyperphosphorylation. Finally, lomerizine abolished the LPS-mediated activation of GSK3α/β and upregulation of DYRK1A, which is responsible for tau hyperphosphorylation, in wild-type mice. Discussion: These data suggest that lomerizine attenuates LPS-mediated neuroinflammatory responses and tau hyperphosphorylation and is a potential drug for neuroinflammation- or tauopathy-associated diseases. [ABSTRACT FROM AUTHOR]

Background: Intellectual developmental disorder 7 (also named DYRK1A syndrome) is an autosomal dominant disease. The main clinical features of DYRK1A syndrome include intellectual disability, microcephaly, and developmental delay. This study aimed to identify pathogenic variants in a Chinese girl with developmental delay, impaired social interaction, and autistic behavior. Case presentation: The case was a 6-year-old girl. Clinical symptoms of the patient mainly included developmental delay, seizures, autistic behavior and impaired social interaction. The patient presented with microcephaly, bushy eyebrows, a short lingual frenum, binocular esotropia, bilateral valgus and external rotation, and walked with an abnormal gait. Using whole-exome sequencing, we identified a 9,424 bp de novo heterozygous deletion (containing coding exons 10, 11, and 12, and partial sequences of non-coding exon 12) in DYRK1A, which is responsible for DYRK1A syndrome. The DYRK1A variant is classified as pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Conclusions: The findings of this study augment the data regarding the pathogenic variants of DYRK1A and provide important information for molecular diagnosis. [ABSTRACT FROM AUTHOR]

PURPOSE: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. METHODS: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1as role in renal development. RESULTS: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. CONCLUSION: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

The homeodomain-interacting protein kinase (HIPK) family is comprised of four nuclear protein kinases, HIPK1-4. HIPK proteins phosphorylate a diverse range of transcription factors involved in cell proliferation, differentiation, and apoptosis. HIPK2, thus far the best-characterized member of this largely understudied family of protein kinases, plays a role in the activation of p53 in response to DNA damage. Despite this tumor-suppressor function, HIPK2 is also found overexpressed in several cancers, and its hyperactivation causes chronic fibrosis. There are currently no structures of HIPK2 or of any other HIPK kinase. Here, we report the crystal structure of HIPK2's kinase domain bound to CX-4945, a casein kinase 2α (CK2α) inhibitor currently in clinical trials against several cancers. The structure, determined at 2.2 Å resolution, revealed that CX-4945 engages the HIPK2 active site in a hybrid binding mode between that seen in structures of CK2α and Pim1 kinases. The HIPK2 kinase domain crystallized in the active conformation, which was stabilized by phosphorylation of the activation loop. We noted that the overall kinase domain fold of HIPK2 closely resembles that of evolutionarily related dual-specificity tyrosine-regulated kinases (DYRKs). Most significant structural differences between HIPK2 and DYRKs included an absence of the regulatory N-terminal domain and a unique conformation of the CMGC-insert region and of a newly defined insert segment in the αC-β4 loop. This first crystal structure of HIPK2 paves the way for characterizing the understudied members of the HIPK family and for developing HIPK2-directed therapies for managing cancer and fibrosis.

Summary: Background: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. Methods: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established “biological-ageing-clock”) in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. Findings: Biological age in adults with DS is (on average) 18.4–19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. Interpretation: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. Funding: Main funding came from the “Research Cooperability” Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014–2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the “Acknowledgements”.

Objective: To comprehensively evaluate the effectiveness and safety of lorecivivint inhibitors in the treatment of osteoarthritis through meta-analysis. Methods: A comprehensive literature search on lorecivivint inhibitors in osteoarthritis was performed using electronic databases such as PubMed, Embase, Web of Science, and CochraneLibrary up to July 30, 2022. Two reviewers independently screened, evaluated, and reviewed the eligible studies. Data analysis and processing were carried out using RevMan 5.4 software. Results: A total of six studies involving 3056 participants were included. Meta-analysis showed that compared with the control group, lorecivivint significantly increased WOMAC discomfort (0.03 mg Week 12) (MD = −0.21, 95% CI [-1.94 – 1.53]; P = 0.81), WOMAC function (0.07 mg Week 24) (MD = −1.81, 95% CI [-4.74 – 1.12]; P = 0.23) and Joint space width (0.23 mg Week 24) (MD = −1.16, 95% CI [-3.69 – 1.38]; P = 0.37). Conclusion: A new treatment method combining Wnt pathway modulators with intra-articular CLK2/DYRK1A inhibitors could be a promising therapy for treating osteoarthritis. Lorecivivint was found to significantly improve WOMAC discomfort, WOMAC function, and joint space width in osteoarthritis patients. It is anticipated to be a reliable, safe, and effective treatment option for osteoarthritis with significant therapeutic utility and potential applications.

DYRK1A‐related intellectual disability is a recently described syndrome characterized by microcephaly, global developmental delay, impaired speech development, and distinctive facial features, which let to define it as a recognizable syndrome. Here we report four new patients of different ethnicity, broadening the clinical phenotype of the condition and highlighting how ethnic influences in the facial appearance could make it less recognizable. [ABSTRACT FROM AUTHOR]

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, which is characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by an increased dosage of Dyrk1a and at least three other genes. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurodegenerative disease with more than 50 million people suffer from it. Unfortunately, none of the currently available drugs is able to improve cognitive impairment in AD patients. Urolithin A (UA) is a metabolite obtained from ellagic acid and ellagitannin through the intestinal flora, and it has antioxidant and anti-inflammatory properties. Previous reports found that UA had neuroprotective effects in an AD animal model, but the detailed mechanism still needs to be elucidated. In this study, we performed kinase-profiling to show that dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is the main target of UA. Studies showed that the level of DYRK1A in AD patients' brains was higher than that of healthy people, and it was closely related to the occurrence and progression of AD. Our results revealed that UA significantly reduced the activity of DYRK1A, which led to de-phosphorylation of tau and further stabilized microtubule polymerization. UA also provided neuroprotective effects by inhibiting the production of inflammatory cytokines caused by Aβ. We further showed that UA significantly improved memory impairment in an AD-like mouse model. In summary, our results indicate that UA is a DYRK1A inhibitor that may provide therapeutic advantages for AD patients. [ABSTRACT FROM AUTHOR]

Natural polyphenol derivatives such as those found in green tea have been known for a long time for their useful therapeutic activity. Starting from EGCG, we have discovered a new fluorinated polyphenol derivative (1c) characterized by improved inhibitory activity against DYRK1A/B enzymes and by considerably improved bioavailability and selectivity. DYRK1A is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome and Alzheimer's disease), oncology, and type 2 diabetes (pancreatic β-cell expansion). Systematic structure–activity relationship (SAR) on trans-GCG led to the discovery that the introduction of a fluoro atom in the D ring and methylation of the hydroxy group from para to the fluoro atom provide a molecule (1c) with more desirable drug-like properties. Owing to its good ADMET properties, compound 1c showed excellent activity in two in vivo models, namely the lipopolysaccharide (LPS)-induced inflammation model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model for Parkinson's disease. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases, while metastasis is considered the leading cause of HCC-related death. However, the currently available treatment strategies for efficient suppression of metastasis are limited. Therefore, novel therapeutic targets to inhibit metastasis and effectively treat HCC are urgently required. Methods Wound healing and Transwell assays were used to determine the migration and invasion abilities of HCC cells in vitro. Quantitative real-time PCR (qRT-PCR), protein array, immunofluorescence, and immunoprecipitation experiments were used to study the mechanism of DYRK1A-mediated metastasis. A tail vein metastasis model and H&E staining were utilized to assess metastatic potential in vivo. Results The results of the current study demonstrated that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) was upregulated in HCC tissues compared with normal liver tissues. Additionally, the level of DYRK1A was increased in primary HCC tissues of patients with metastasis compared with those of patients without metastasis, and DYRK1A overexpression correlated with worse outcomes in liver cancer patients. Gain- and loss-of-function studies suggested that DYRK1A enhanced the invasion and migration abilities of HCC cells by promoting epithelial-mesenchymal transition (EMT). Regarding the promoting effect of DYRK1A on cell invasion, the results showed that DYRK1A was coexpressed with TGF-β/SMAD and STAT3 signalling components in clinical tumour samples obtained from patients with HCC. DYRK1A also activated TGF-β/SMAD signalling by interacting with tuberous sclerosis 1 (TSC1) and enhanced metastasis of HCC cells by activating STAT3. Furthermore, DYRK1A promoted EMT by cooperatively activating STAT3/SMAD signalling. Conclusion Overall, the present study not only uncovered the promoting effect of DYRK1A on HCC metastasis and revealed the mechanism but also provided a new approach to predict and treat metastatic HCC.

Atrioventricular septal defect (AVSD) is a deleterious subtype of congenital heart diseases (CHD) characterized by atrioventricular canal defect. The pathogenic genetic changes of AVSD remain elusive, particularly for copy number variation (CNV), a large segment variation of the genome, which is one of the major forms of genetic variants resulting in congenital heart diseases. In the present study, we recruited 150 AVSD cases and 100 healthy subjects as controls for whole exome sequencing (WES). We identified total 4255 rare CNVs using exon Hidden Markov model (XHMM) and screened rare CNVs by eliminating common CNVs based on controls and Database of Genomic Variants (DGV). Each patient contained at least 9 CNVs, and the CNV burden was prominently presented in chromosomes 19,22,21&16. Small CNVs (<500 kb) were frequently observed. By leveraging gene-based burden test, we further identified 20 candidate AVSD-risk genes. Among them, DYRK1A, OBSCN and TTN were presented in the core disease network of CHD and highly and dynamically expressed in the heart during the development, which indicated they possessed the high potency to be AVSDsusceptible genes. These findings not only provided a roadmap for finally unveiling the genetic cause of AVSD, but also provided more resources and proofs for clinical genetics. [ABSTRACT FROM AUTHOR]

Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeastbased pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer's disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS. [ABSTRACT FROM AUTHOR]

Dysregulated differentiation of naïve CD4+ T cells into T helper 17 (Th17) cells is likely a key factor predisposing to many autoimmune diseases. Therefore, better understanding how Th17 differentiation is regulated is essential to identify novel therapeutic targets and strategies to identify individuals at high risk of developing autoimmunity. Here, we extend our prior work using chemical inhibitors to provide mechanistic insight into a novel regulator of Th17 differentiation, the kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). We generated a conditional knockout mouse model to validate DYRK1A as a regulator of Th17 differentiation that acts in a dose-dependent fashion at least in part by modulating interleukin (IL)-6 signaling through multiple mechanisms. We identified a new role for DYRK1A in regulating surface expression of IL-6 receptor subunits in naïve CD4+ T cells, consistent with DYRK1A's impact on Th17 differentiation. Physiologic relevance is supported by findings in people with Down syndrome, in which increased expression of DYRK1A, encoded on chromosome 21, is linked to increased IL-6 responsiveness. Our findings highlight DYRK1A as a druggable target of broad therapeutic and prognostic interest in autoimmunity and immune function., (© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists.)

Intervening in mitochondrial oxidative phosphorylation (OXPHOS) has emerged as a potential therapeutic strategy for certain types of cancers. Employing kinome-based CRISPR screen, we find that knockout of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) synergizes with OXPHOS inhibitor IACS-010759 in liver cancer cells. Targeting DYRK1A combined with OXPHOS inhibitors activates TGF-β signaling, which is crucial for OXPHOS-inhibition-triggered cell death. Mechanistically, upregulation of glutamine transporter solute carrier family 1 member 5 (SLC1A5) transcription compensates for the increased glutamine requirement upon OXPHOS inhibition. DYRK1A directly phosphorylates SMAD3 Thr132, thereby suppressing the negative impact of TGF-β signaling on transcription of SLC1A5, leading to intrinsic resistance of liver cancer cells to OXPHOS inhibition. Moreover, we demonstrate the therapeutic efficacy of IACS-010759 in combination with DYRK1A inhibition in multiple liver cancer models, including xenografts, patient-derived xenografts, and spontaneous tumor model. Our study elucidates how the DYRK1A-TGF-β signaling axis controls the response of tumor cells to OXPHOS inhibition and provides valuable insights into targeting OXPHOS for liver cancer therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeast-based pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS.

Alzheimer’s disease (AD) is a neurological disorder caused by the abnormal accumulation of hyperphosphorylated proteins. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual phosphorylation enzyme which phosphorylates the amyloid-β (Aβ) and neurofibrillary tangles (NFTs). A high throughput virtual screening approach was applied to screen a library of 98,071 compounds against DYRK1A using different programs including AutoDock Vina, Smina, and idock. Based on the binding affinities, we selected 330 compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Various pharmacokinetics parameters were predicted using the admetSAR server, and based on the pharmacokinetics results, 14 compounds were selected for cross-docking analysis using AutoDock. Cross-docking analysis revealed four compounds, namely, ZINC3843365 (−11.07 kcal/mol−1), ZINC2123081 (−10.93 kcal/mol−1), ZINC5220992 (−10.63 kcal/mol−1), and ZINC68569602 (−10.35 kcal/mol−1), which had the highest negative affinity scores compared to the 10 other molecules analyzed. Density functional theory (DFT) analysis was conducted for all the four top-ranked compounds. The molecular interaction stability of these four compounds with DYRK1A has been evaluated using molecular dynamics (MD) simulations on 100 nanoseconds followed by principal component analysis (PCA) and binding free energy calculations. The Gibbs free energy landscape analysis suggested the metastable state and folding pattern of selected docking complexes. Based on the present study outcome, we propose four antagonists, viz., ZINC3843365, ZINC2123081, ZINC5220992, and ZINC68569602 as potential inhibitors against DYRK1A and to reduce the amyloid-β and neurofibrillary tangle burden. These screened molecules can be further investigated using a number of in vitro and in vivo experiments.

DYRK1A syndrome has been extensively studied primarily with regard to neurologic and other phenotypic features such as skeleton and craniofacial alterations. In the present paper, we aim to highlight unusual anomalies associated with a DYRK1A mutation: a 17-year-old female patient with language and cognitive delay, microcephaly, and an autistic disorder, who was operated upon for spleen torsion with anomalous gut fixation.

IntroductionDYRK1A is a dual-specificity kinase that is overexpressed in Down syndrome (DS) and plays a key role in neurogenesis, neuronal differentiation and function, cognitive phenotypes, and aging. Dyrk1A has also been implicated in cerebellar abnormalities observed in association with DS, and normalization of Dyrk1A dosage rescues granular and Purkinje cell densities in a trisomic DS mouse model. However, the underlying molecular mechanisms governing these processes are unknown.MethodsTo shed light on the effects of Dyrk1A overexpression in the cerebellum, here we investigated the cerebellar proteome in transgenic Dyrk1A overexpressing mice in basal conditions and after treatment with green tea extract containing epigallocatechin-3-gallate (EGCG), a DYRK1A inhibitor.Results and DiscussionOur results showed that Dyrk1A overexpression alters oxidative phosphorylation and mitochondrial function in the cerebellum of transgenic mice. These alterations are significantly rescued upon EGCG-containing green tea extract treatment, suggesting that its effects in DS could depend in part on targeting mitochondria, as shown by the partially restoration by the treatment of the increased mtDNA copy number in TG non-treated mice.

Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-Idependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1/PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing that i) high expression levels of TAP1, Tapasin and Lmp2 was observed in melanoma patients that respond to anti-PD1; ii) the survival is significantly improved in melanoma patients who express high MHC-I signature relative to those expressing low MHC-I signature; and iii) high expression of MHC-I signature in melanoma patients was correlated with increased expression of CD8 and NK cell markers and overexpression of proinflammatory chemokines involved in the recruitment of CD8+ T cells. [ABSTRACT FROM AUTHOR]

NFATs and FOXP3 are linked with impaired regulatory T‐cells (Tregs) in generalized vitiligo (GV). To elucidate calcium mediated NFATc1 signalling pathway and its effect on Treg suppressive capacity in GV. Calcium levels, calcineurin, NFATc1 and GSK‐3β activity and cell proliferation were assessed in 52 GV patients and 50 controls by calcium assay kit, calcineurin phosphatase assay kit, TransAM NFATc1 kit, GSK‐3β ELISA and BrdU cell proliferation assay. Transcripts (CNB, CAM, GSK3B, DYRK1A and calcium channel genes) and protein (IFN‐γ, IL‐10 and TGF‐β) expressions were assessed by qPCR and ELISA, respectively. Reduced plasma and intracellular Tregs calcium levels and ORAI1 transcripts suggested altered calcium homeostasis in GV Tregs (p = 0.00387, p = 0.0048, p < 0.0001), which led to decreased calcineurin and NFATc1 activity in GV Tregs (p = 0.0299, p < 0.0001). CNB and CAM transcripts were reduced in GV Tregs (p < 0.0001, p = 0.0004). GSK‐3β activity, GSK3B and DYRK1A transcripts significantly increased in GV Tregs (p = 0.0134, p < 0.0001 and p < 0.0001). Plasma (p = 0.0225, p = 0.032) and intracellular Treg (p = 0.0035, p = 0.005) calcium levels, calcineurin (p = 0.001) and NFATc1 (p = 0.001, p < 0.0001) activity and ORAI1 (p = 0.0093, p < 0.0001), CAM and CNB (p = 0.0214) transcripts significantly decreased in active vitiligo (AV) and severe GV (sGV) Tregs. Calcium treatment significantly increased intracellular calcium and ORAI1 transcripts in GV Tregs (p = 0.0042, p = 0.0035). Moreover, calcium treatment enhanced calcineurin and NFATc1 activity in GV Tregs (p = 0.0128, p < 0.0001). Remarkably, calcium treatment increased Treg mediated suppression of CD4+ and CD8+ T‐cells (p = 0.015, p = 0.006) in GV and increased Tregs associated cytokines: IL‐10 (p = 0.0323, p = 0.009), TGF‐β (p = 0.0321, p = 0.01) and decreased IFN‐γ production (p = 0.001, p = 0.016) by CD4+ and CD8+ T‐cells. Intracellular calcium levels positively correlated with calcineurin (r = 0.83; p < 0.0001) and NFATc1 (r = 0.61; p < 0.0001) activity, suggesting the enhanced Treg immunosuppressive capacity after calcium treatment. Our study for the first time suggests that reduced plasma calcium and ORAI1 transcripts are linked to calcium uptake defects in Tregs, which leads to reduced calcineurin and NFATc1 activation, thereby contributing to decreased Tregs immunosuppressive capacity in GV. Elevated GSK‐3β activity and GSKB and DYRK1A transcripts are involved in reduced NFATc1 activity in GV Tregs. Overall, the study suggests that calcium‐NFATc1‐signalling pathway is likely to be involved in defective Tregs function and can be implicated for development of effective Treg mediated therapeutics for GV. [ABSTRACT FROM AUTHOR]

DYRK1A and Wiedemann–Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient‐driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management. [ABSTRACT FROM AUTHOR]

Abstract Glioblastoma (GBM) is the most aggressive glioma, and is prone to develop resistance to chemotherapy and radiotherapy; hence, patients with glioblastoma have a high recurrence rate and a low 1‐year survival rate. In addition, the pathogenesis of glioblastoma is complex and largely unknown, and the available treatments are limited. Here, we uncovered a fundamental role of DYRK1A in regulating NFATC1 in GBMs. We found that DYRK1A was highly expressed in glioma and glioblastoma cells, and its expression was positively correlated with that of NFATC1. Moreover, inhibition of DYRK1A promoted NFATC1 degradation in GBM cells and sharply reduced the transactivation of NFATC1, not only by decreasing the expression of NFATC1‐targeted genes, but also by reducing the luciferase activity, and vice versa. However, DYRK1A had the opposite effect on NFATC2. Most importantly, our data suggest that DYRK1A inhibition reduces glioblastoma migration. Polypeptides derived from the DYRK1A‐targeted motif of NFATC1, by competitively blocking DYRK1A kinase activity on NFATC1, clearly destabilized NFATC1 protein and impaired glioblastoma migration. We propose that the recovery of NFATC1 stability is a key oncogenic event in a large proportion of gliomas, and pharmacological inhibition of DYRK1A by polypeptides could represent a promising therapeutic intervention for GBM.

The N-terminal half of adenovirus e1a assembles multimeric complexes with host proteins that repress innate immune responses and force host cells into S-phase. In contrast, the functions of e1a's C-terminal interactions with FOXK, DCAF7, and CtBP are unknown. We found that these interactions modulate RAS signaling, and that a single e1a molecule must bind all three of these host proteins to suppress activation of a subset of IFN-stimulated genes (ISGs). These ISGs were otherwise induced in primary respiratory epithelial cells at 12 hr p.i. This delayed activation of ISGs required IRF3 and coincided with an ∼10-fold increase in IRF3 from protein stabilization. The induced IRF3 bound to chromatin and localized to the promoters of activated ISGs. While IRF3, STAT1/2, and IRF9 all greatly increased in concentration, there were no corresponding mRNA increases, suggesting that e1a regulates the stabilities of these key activators of innate immune responses, as shown directly for IRF3.

Harmine is a dual-specificity tyrosine-regulated kinase 1A (DYRK1A) inhibitor that displays a number of biological and pharmacological properties. Also referred to as ACB1801 molecule, we have previously reported that harmine increases the presentation of major histocompatibility complex (MHC)-I-dependent antigen on melanoma cells. Here, we show that ACB1801 upregulates the mRNA expression of several proteins of the MHC-I such as Transporter Associated with antigen Processing TAP1 and 2, Tapasin and Lmp2 (hereafter referred to as MHC-I signature) in melanoma cells. Treatment of mice bearing melanoma B16-F10 with ACB1801 inhibits the growth and weight of tumors and induces a profound modification of the tumor immune landscape. Strikingly, combining ACB1801 with anti-PD1 significantly improves its therapeutic benefit in B16-F10 melanoma-bearing mice. These results suggest that, by increasing the MHC-I, ACB1801 can be combined with anti-PD1/PD-L1 therapy to improve the survival benefit in cancer patients displaying a defect in MHC-I expression. This is further supported by data showing that i) high expression levels of TAP1, Tapasin and Lmp2 was observed in melanoma patients that respond to anti-PD1; ii) the survival is significantly improved in melanoma patients who express high MHC-I signature relative to those expressing low MHC-I signature; and iii) high expression of MHC-I signature in melanoma patients was correlated with increased expression of CD8 and NK cell markers and overexpression of proinflammatory chemokines involved in the recruitment of CD8+ T cells.

Background: Currently, there are no efficient therapies for Alzheimer's disease (AD) among the elderly, although it is the most common etiology of dementia among the elderly. Quercetin, which has a variety of therapeutic properties, may pave the way for novel approaches to AD treatment. In the AD patients' frontal cortex, current study aims to identify the potential mechanisms of quercetin's pharmacological targets. Materials and methods: The pharmacological targets of quercetin have been studied from DrugBank and SwissTarget. In order to distinguish AD-associated genes targeted by quercetin (Q-ADGs), we utilized an integrated intersection of gene expressions of the frontal cortex in combination with transcriptome analysis. To detect cortex-related Q-ADGs and immune-related Q-ADGs, a drug screening database and the immune infiltration analysis was utilized. The Q-ADGs were then linked with the AD severity scores (MMSE scores) to find severity-associated Q-ADGs. In addition, the miRNA-seq datasets were examined to identify severity-associated Q-ADG-miRNAs. Twelve genes, more frequently related to AD by previous studies among all the genes identified in the present study, were subjected to the verification of qRT-PCR in AD cell model. Results: In the frontal lobe of AD, 207 Q-ADGs were discovered and found that axonogenesis, glial differentiation, and other biological processes had been enriched. There were 155 immune-related Q-ADGs (e.g., COX2, NOS2, HMGB1) and 65 cortex-related Q-ADGs (e.g., FOXO1, CXCL16, NOTCH3). Sixteen Q-ADGs (e.g., STAT3, RORA, BCL6) and 28 miRNAs (e.g., miR-142-5p, miR-17-5p) were found to be related to MMSE scores. In the qRT-PCR results, six out of twelve genes were significantly regulated by quercetin. DYRK1A, FOXO1, NOS2, NGF, NQO1, and RORA genes were novel target of quercetin in AD. DYRK1A, NOS2, and NQO1 genes targeted by quercetin have benefits in the treatment of AD. However, FOXO1, NGF, and RORA genes targeted by quercetin might have a negative impact on AD. Conclusion: The role of quercetin in AD appears to be multifaceted, and it can affect patients' frontal cortex in a variety of pathways, such as axonogenesis, immune infiltration, and glial cell differentiation. DYRK1A, NOS2, and NQO1 might be potential novel effective drug targets for quercetin in AD. [ABSTRACT FROM AUTHOR]

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation (AppNL-F>) to determine how chromosome 21 genes, other than APP, modulate APP/Aβ in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aβ accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Ab accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2. Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aβ in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP. [ABSTRACT FROM AUTHOR]

Dyrk1a triplication in Down's syndrome and its overexpression in Alzheimer's disease suggest a role for increased DYRK1A activity in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of Alzheimer's disease, which lead to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in human neurons remains unknown. From a proteomic dataset of human cerebral organoids treated with harmine, a DYRK1A inhibitor, we found expression changes in protein clusters associated with the control of microtubule-based transport and in close interaction with the APP vesicle. Live imaging of APP axonal transport in human-derived neurons treated with harmine or overexpressing a dominant negative DYRK1A revealed a reduction in APP vesicle density and enhanced the stochastic behavior of retrograde vesicle transport. Moreover, harmine increased the fraction of slow segmental velocities and changed speed transitions supporting a DYRK1A-mediated effect in the exchange of active motor configuration. Contrarily, the overexpression of DYRK1A in human polarized neurons increased the axonal density of APP vesicles and enhanced the processivity of retrograde APP. In addition, increased DYRK1A activity induced faster retrograde segmental velocities together with significant changes in slow to fast anterograde and retrograde speed transitions, suggesting the facilitation of the active motor configuration. Our results highlight DYRK1A as a modulator of the axonal transport machinery driving APP intracellular distribution in neurons, and stress DYRK1A inhibition as a putative therapeutic intervention to restore APP axonal transport in Down's syndrome and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The increasing population will challenge healthcare, particularly because the worldwide population has never been older. Therapeutic solutions to age-related disease will be increasingly critical. Kinases are key regulators of human health and represent promising therapeutic targets for novel drug candidates. The dual-specificity tyrosine-regulated kinase (DYRKs) family is of particular interest and, among them, DYRK1A has been implicated ubiquitously in varied human diseases. Herein, we focus on the characteristics of DYRK1A, its regulation and functional role in different human diseases, which leads us to an overview of future research on this protein of promising therapeutic potential. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as Amyloid Precursor Protein (APP) into Amyloid-ß and Microtubule Associated Protein Tau (MAPT) gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of APP and other AD-associated genes, such as DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-ß mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-ß and DYRK1a mediated phenotype. To address these outstanding questions, we characterised Drosophila models with targeted overexpression of human Tau, human Amyloid-ß or the fly orthologue of DYRK1A, called minibrain (mnb). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau [at serine (S) 262]. PST-001 reduced degeneration caused by human Tau, Amyloid-ß or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology. [ABSTRACT FROM AUTHOR]

DYRK1A haploinsufficiency syndrome is a well‐established neurodevelopmental disorder, but detailed information on the range of cognitive and behavioral issues associated with the condition is limited. We studied 24 participants with likely pathogenic or pathogenic variants in DYRK1A through the Simons Searchlight study and systematically assessed their medical history and development using standardized instruments: Vineland Adaptive Behavior Scale II (VABS‐II) and Child Behavior Checklists/1.5‐5 and 6‐18 (CBCL/1.5‐5, CBCL/6‐18). All of the individuals in the cohort had neurological manifestations including intellectual disability or developmental delay, microcephaly, autism spectrum disorder, and/or seizures. The severity of the neurodevelopmental disorder was variable with a few children scoring in the moderately low range on the adaptive behavior composite score on the VABS‐II. This study confirms the association of DYRK1A haploinsufficiency with neurodevelopmental disabilities, microcephaly, autism spectrum disorder, and epilepsy and quantifies the range of adaptive behaviors. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a complex genetic condition due to an additional copy of human chromosome 21, which results in the deregulation of many genes. In addition to the intellectual disability associated with DS, adults with DS also have an ultrahigh risk of developing early onset Alzheimer's disease dementia. DYRK1A, a proline-directed serine/threonine kinase, whose gene is located on chromosome 21, has recently emerged as a promising plasma biomarker in patients with sporadic Alzheimer's disease (AD). The protein DYRK1A is truncated in symptomatic AD, the increased truncated form being associated with a decrease in the level of full-length form. Activity-dependent neuroprotective protein (ADNP), a key protein for the brain development, has been demonstrated to be a useful marker for symptomatic AD and disease progression. In this study, we evaluated DYRK1A and ADNP in CSF and plasma of adults with DS and explored the relationship between these proteins. We used mice models to evaluate the effect of DYRK1A overexpression on ADNP levels and then performed a dual-center cross-sectional human study in adults with DS in Barcelona (Spain) and Paris (France). Both cohorts included adults with DS at different stages of the continuum of AD: asymptomatic AD (aDS), prodromal AD (pDS), and AD dementia (dDS). Non-trisomic controls and patients with sporadic AD dementia were included for comparison. Full-form levels of DYRK1A were decreased in plasma and CSF in adults with DS and symptomatic AD (pDS and dDS) compared to aDS, and in patients with sporadic AD compared to controls. On the contrary, the truncated form of DYRK1A was found to increase both in CSF and plasma in adults with DS and symptomatic AD and in patients with sporadic AD with respect to aDS and controls. ADNP levels showed a more complex structure. ADNP levels increased in aDS groups vs. controls, in agreement with the increase in levels found in the brains of mice overexpressing DYRK1A. However, symptomatic individuals had lower levels than aDS individuals. Our results show that the comparison between full-length and truncated-form levels of DYRK1A coupled with ADNP levels could be used in trials targeting pathophysiological mechanisms of dementia in individuals with DS. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer cases, while metastasis is considered the leading cause of HCC-related death. However, the currently available treatment strategies for efficient suppression of metastasis are limited. Therefore, novel therapeutic targets to inhibit metastasis and effectively treat HCC are urgently required. Methods: Wound healing and Transwell assays were used to determine the migration and invasion abilities of HCC cells in vitro. Quantitative real-time PCR (qRT-PCR), protein array, immunofluorescence, and immunoprecipitation experiments were used to study the mechanism of DYRK1A-mediated metastasis. A tail vein metastasis model and H&E staining were utilized to assess metastatic potential in vivo. Results: The results of the current study demonstrated that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) was upregulated in HCC tissues compared with normal liver tissues. Additionally, the level of DYRK1A was increased in primary HCC tissues of patients with metastasis compared with those of patients without metastasis, and DYRK1A overexpression correlated with worse outcomes in liver cancer patients. Gain- and loss-of-function studies suggested that DYRK1A enhanced the invasion and migration abilities of HCC cells by promoting epithelial-mesenchymal transition (EMT). Regarding the promoting effect of DYRK1A on cell invasion, the results showed that DYRK1A was coexpressed with TGF-β/SMAD and STAT3 signalling components in clinical tumour samples obtained from patients with HCC. DYRK1A also activated TGF-β/SMAD signalling by interacting with tuberous sclerosis 1 (TSC1) and enhanced metastasis of HCC cells by activating STAT3. Furthermore, DYRK1A promoted EMT by cooperatively activating STAT3/SMAD signalling. Conclusion: Overall, the present study not only uncovered the promoting effect of DYRK1A on HCC metastasis and revealed the mechanism but also provided a new approach to predict and treat metastatic HCC. [ABSTRACT FROM AUTHOR]

Summary: Background: While the adult mammalian heart undergoes only modest renewal through cardiomyocyte proliferation, boosting this process is considered a promising therapeutic strategy to repair cardiac injury. This study explored the role and mechanism of dual-specificity tyrosine regulated kinase 1A (DYRK1A) in regulating cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction (MI). Methods: DYRK1A-knockout mice and DYRK1A inhibitors were used to investigate the role of DYRK1A in cardiomyocyte cell cycle activation and cardiac repair following MI. Additionally, we explored the underlying mechanisms by combining genome-wide transcriptomic, epigenomic, and proteomic analyses. Findings: In adult mice subjected to MI, both conditional deletion and pharmacological inhibition of DYRK1A induced cardiomyocyte cell cycle activation and cardiac repair with improved cardiac function. Combining genome-wide transcriptomic and epigenomic analyses revealed that DYRK1A knockdown resulted in robust cardiomyocyte cell cycle activation (shown by the enhanced expression of many genes governing cell proliferation) associated with increased deposition of trimethylated histone 3 Lys4 (H3K4me3) and acetylated histone 3 Lys27 (H3K27ac) on the promoter regions of these genes. Mechanistically, via unbiased mass spectrometry, we discovered that WD repeat-containing protein 82 and lysine acetyltransferase 6A were key mediators in the epigenetic modification of H3K4me3 and H3K27ac and subsequent pro-proliferative transcriptome and cardiomyocyte cell cycle activation. Interpretation: Our results reveal a significant role of DYRK1A in cardiac repair and suggest a drug target with translational potential for treating cardiomyopathy. Funding: This study was supported in part by grants from the National Natural Science Foundation of China (81930008, 82022005, 82070296, 82102834), National Key R&D Program of China (2018YFC1312700), Program of Innovative Research Team by the National Natural Science Foundation (81721001), and National Institutes of Health (5R01DK039308-31, 7R37HL023081-37, 5P01HL074940-11).

Plant-derived polyphenols flavonoids are increasingly being recognized for their medicinal potential. These bioactive compounds derived from plants are gaining more interest in ameliorating adverse health risks because of their low toxicity and few side effects. Among them, therapeutic approaches demonstrated the efficacy of catechins, a major group of flavonoids, in reverting several aspects of Down syndrome, the most common genomic disorder that causes intellectual disability. Down syndrome is characterized by increased incidence of developing Alzheimer's disease, obesity, and subsequent metabolic disorders. In this focused review, we examine the main effects of catechins on comorbidities linked with Down syndrome. We also provide evidence of catechin effects on DYRK1A, a dosage-sensitive gene encoding a protein kinase involved in brain defects and metabolic disease associated with Down syndrome. [ABSTRACT FROM AUTHOR]

Hertwig's Εpithelial Root Sheath (HΕRS) has a major function in the developing tooth roots. Earlier research revealed that it undergoes epithelial–mesenchymal transition, a vital process for the morphogenesis and complete development of the tooth and its surrounding periodontium. Few studies have demonstrated the role of HERS in cementogenesis through ΕMΤ. The background of this in-silico system biology approach is to find a hub protein and gene involved in the EMT of HERS that may uncover novel insights in periodontal regenerative drug targets. The protein and gene list involved in epithelial–mesenchymal transition were obtained from literature sources. The protein interaction was constructed using STRING software and the protein interaction network was analyzed. Molecular docking simulation checks the binding energy and stability of protein-ligand complex. Results revealed the hub gene to be DYRK1A(Hepcidin), and the ligand was identified as isoetharine. SΤRIΝG results showed a confidence cutoff of 0.9 in sensitivity analysis with a condensed protein interaction network. Overall, 98 nodes from 163 nodes of expected edges were found with an average node degree of 11.9. Docking results show binding energy of −4.70, and simulation results show an RMSD value of 5.6 Å at 50 ns. Isoetharine could be a potential drug for periodontal regeneration. [ABSTRACT FROM AUTHOR]

Simple Summary: The dual-specificity tyrosine-regulated kinase (DYRK) family has been implicated in various diseases, including cancer. However, its role in colorectal cancer has not been elucidated. In this research, we used publicly available web-based tools to investigate DYRKs status in colorectal cancer. Our results showed that among DYRKs, only DYRK1A was upregulated significantly in late tumor stages, and it is associated with poor prognosis for colorectal cancer patients. These finding comprehensively characterized DYRK1A as a potential new therapeutic approach in CRC, especially in late tumor stages. Colorectal cancer (CRC) is the third most common cancer worldwide and has an increasing incidence in younger populations. The dual-specificity tyrosine-regulated kinase (DYRK) family has been implicated in various diseases, including cancer. However, the role and contribution of the distinct family members in regulating CRC tumorigenesis has not been addressed yet. Herein, we used publicly available CRC patient datasets (TCGA RNA sequence) and several bioinformatics webtools to perform in silico analysis (GTEx, GENT2, GEPIA2, cBioPortal, GSCALite, TIMER2, and UALCAN). We aimed to investigate the DYRK family member expression pattern, prognostic value, and oncological roles in CRC. This study shed light on the role of distinct DYRK family members in CRC and their potential outcome predictive value. Based on mRNA level, DYRK1A is upregulated in late tumor stages, with lymph node and distant metastasis. All DYRKs were found to be implicated in cancer-associated pathways, indicating their key role in CRC pathogenesis. No significant DYRK mutations were identified, suggesting that DYRK expression variation in normal vs. tumor samples is likely linked to epigenetic regulation. The expression of DYRK1A and DYRK3 expression correlated with immune-infiltrating cells in the tumor microenvironment and was upregulated in MSI subtypes, pointing to their potential role as biomarkers for immunotherapy. This comprehensive bioinformatics analysis will set directions for future biological studies to further exploit the molecular basis of these findings and explore the potential of DYRK1A modulation as a novel targeted therapy for CRC. [ABSTRACT FROM AUTHOR]

Dual-specific tyrosine phosphorylation regulated kinase 1 (DYRK1A) has been regarded as a potential therapeutic target of neurodegenerative diseases, and considerable progress has been made in the discovery of DYRK1A inhibitors. Identification of pharmacophoric fragments provides valuable information for structure- and fragment-based design of potent and selective DYRK1A inhibitors. In this study, seven machine learning methods along with five molecular fingerprints were employed to develop qualitative classification models of DYRK1A inhibitors, which were evaluated by cross-validation, test set, and external validation set with four performance indicators of predictive classification accuracy (CA), the area under receiver operating characteristic (AUC), Matthews correlation coefficient (MCC), and balanced accuracy (BA). The PubChem fingerprint-support vector machine model (CA = 0.909, AUC = 0.933, MCC = 0.717, BA = 0.855) and PubChem fingerprint along with the artificial neural model (CA = 0.862, AUC = 0.911, MCC = 0.705, BA = 0.870) were considered as the optimal modes for training set and test set, respectively. A hybrid data balancing method SMOTETL, a combination of synthetic minority over-sampling technique (SMOTE) and Tomek link (TL) algorithms, was applied to explore the impact of balanced learning on the performance of models. Based on the frequency analysis and information gain, pharmacophoric fragments related to DYRK1A inhibition were also identified. All the results will provide theoretical supports and clues for the screening and design of novel DYRK1A inhibitors. [ABSTRACT FROM AUTHOR]

Objective: Mcl-1 overexpression confers acquired resistance to Bcl-2 inhibitors in non-small cell lung cancer (NSCLC), but no direct Mcl-1 inhibitor is currently available for clinical use. Thus, novel therapeutic strategies are urgently needed to target Mcl-1 and sensitize the anti-NSCLC activity of Bcl-2 inhibitors. Methods: Cell proliferation was measured using sulforhodamine B and colony formation assays, and apoptosis was detected with Annexin V-FITC staining. Gene expression was manipulated using siRNAs and plasmids. Real-time PCR and Western blot were used to measure mRNA and protein levels. Immunoprecipitation and immunofluorescence were used to analyze co-localization of dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and Mcl-1. Results: Suppression of DYRK1A resulted in reduced Mcl-1 expression in NSCLC cells, whereas overexpression of DYRK1A significantly increased Mcl-1 expression. Suppression of DYRK1A did not alter Mcl-1 mRNA levels, but did result in an accelerated degradation of Mcl-1 protein in NSCLC cells. Furthermore, DYRK1A mediated proteasome-dependent degradation of Mcl-1 in NSCLC cells, and DYRK1A co-localized with Mcl-1 in NSCLC cells and was co-expressed with Mcl-1 in tumor samples from lung cancer patients, suggesting that Mcl-1 may be a novel DYRK1A substrate. We showed that combined therapy with harmine and Bcl-2 antagonists significantly inhibited cell proliferation and induced apoptosis in NSCLC cell lines as well as primary NSCLC cells. Conclusions: Mcl-1 is a novel DYRK1A substrate, and the role of DYRK1A in promoting Mcl-1 stability makes it an attractive target for decreasing Bcl-2 inhibitor resistance.

Background: All individuals with Down Syndrome (DS) will develop full-blown Alzheimeŕs disease (AD) pathology by age 40, decades before the occurrence of sporadic late-onset AD. Understanding this strong biological relation between age and AD pathology risk in DS is important to accelerate diagnostics, disease monitoring, and treatment. Several genes encoded in chromosome 21 including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) have been proven to contribute to the pathology. A recently validated plasma immunoassay to measure tau phosphorylation at threonine-212 (p-tau212) has very high diagnostic accuracy in detecting AD. P-tau212 is also very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates. Here, we assessed the potential of this biomarker in DSAD and sporadic AD., Methods: Using Simoa technology, we tested p-tau212 and p-tau181 (n=245 for plasma, n=114 matching cerebrospinal fluid (CSF) samples). We used AUC-ROC to examine diagnostic performance and the DeLong test to compare the AUC-ROC differences between methods. Spearman correlation is used to examine correlations. Fold changes relative to median levels were calculated for their respective asymptomatic groups. ANCOVA followed by Tukey posthoc test was used to calculate differences across groups. LOESS was used to determine the temporality of plasma biomarker changes., Results: We have confirmed that p-tau212 has extremely high accuracy in detecting AD-related changes in euploid controls. For the DS population, we observed a strong correlation between plasma and CSF p-tau212 (r=0.867; p<0.001). In prodromal DS (pDS) and dementia DS (dDS), we observed significantly elevated levels of p-tau212 in reference to asymptomatic DS (aDS). The diagnostic accuracy to differentiate between aDS and dDS was AUC=0.91 and AUC = 0.86 in discriminating between DS amyloid positive and amyloid negative participants. Plasma p-tau212 started increasing approximately when people became amyloid PET-positive., Conclusions: We have confirmed that the levels of plasma p-tau212 are increased in the DS population and sporadic AD cases including prodromal and MCI states. Plasma p-tau212 might have utility for theragnostic, monitoring therapy efficacy, and as a target engagement biomarker in clinical trials both in sporadic and DSAD., Competing Interests: MT and PH are employees of Bioventix Plc. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant or at advisory boards for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers. HZ and KB are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. and JF declare a filed patent application (licensed to Adx, EPI8382175 J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Eisai, Fujirebio, Ionis, Laboratorios Carnot, Lilly, Life Molecular Imaging, Lundbeck, Perha, Roche, and, outside the submitted work.The other authors declare no competing interest.

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer’s disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS.

The dual‐specificity tyrosine‐regulated kinases DYRK1A and DYRK1B play a key role in controlling the quiescence‐proliferation switch in cancer cells. Serum reduction of U87MG 2D cultures or multi‐cellular tumour spheroids induced a quiescent like state characterized by increased DYRK1B and p27, and decreased pRb and cyclin D1. VER‐239353 is a potent, selective inhibitor of the DYRK1A and DYRK1B kinases identified through fragment and structure‐guided drug discovery. Inhibition of DYRK1A/B by VER‐239353 in quiescent U87MG cells increased pRb, DYRK1B and cyclin D1 but also increased the cell cycle inhibitors p21 and p27. This resulted in exit from G0 but subsequent arrest in G1. DYRK1A/B inhibition reduced the proliferation of U87MG cells in 2D and 3D culture with greater effects observed under reduced serum conditions. Paradoxically, the induced re‐expression of cell cycle proteins by DYRK1A/B inhibition further inhibited cell proliferation. Cell growth arrest induced in quiescent cells by DYRK1A/B inhibition was reversible through the addition of growth‐promoting factors. DYRK inhibition‐induced DNA damage and synergized with a CHK1 inhibitor in the U87MG spheroids. In vivo, DYRK1A/B inhibition‐induced tumour stasis in a U87MG tumour xenograft model. These results suggest that further evaluation of VER‐239353 as a treatment for glioblastoma is therefore warranted. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive glioma, and is prone to develop resistance to chemotherapy and radiotherapy; hence, patients with glioblastoma have a high recurrence rate and a low 1‐year survival rate. In addition, the pathogenesis of glioblastoma is complex and largely unknown, and the available treatments are limited. Here, we uncovered a fundamental role of DYRK1A in regulating NFATC1 in GBMs. We found that DYRK1A was highly expressed in glioma and glioblastoma cells, and its expression was positively correlated with that of NFATC1. Moreover, inhibition of DYRK1A promoted NFATC1 degradation in GBM cells and sharply reduced the transactivation of NFATC1, not only by decreasing the expression of NFATC1‐targeted genes, but also by reducing the luciferase activity, and vice versa. However, DYRK1A had the opposite effect on NFATC2. Most importantly, our data suggest that DYRK1A inhibition reduces glioblastoma migration. Polypeptides derived from the DYRK1A‐targeted motif of NFATC1, by competitively blocking DYRK1A kinase activity on NFATC1, clearly destabilized NFATC1 protein and impaired glioblastoma migration. We propose that the recovery of NFATC1 stability is a key oncogenic event in a large proportion of gliomas, and pharmacological inhibition of DYRK1A by polypeptides could represent a promising therapeutic intervention for GBM. [ABSTRACT FROM AUTHOR]

Mutations in DYRK1A are a cause of microcephaly, autism spectrum disorder, and intellectual disability; however, the underlying cellular and molecular mechanisms are not well understood. We generated a conditional mouse model using Emx1-cre , including conditional heterozygous and homozygous knockouts, to investigate the necessity of Dyrk1a in the cortex during development. We used unbiased, high-throughput phosphoproteomics to identify dysregulated signaling mechanisms in the developing Dyrk1a mutant cortex as well as classic genetic modifier approaches and pharmacological therapeutic intervention to rescue microcephaly and neuronal undergrowth caused by Dyrk1a mutations. We found that cortical deletion of Dyrk1a in mice causes decreased brain mass and neuronal size, structural hypoconnectivity, and autism-relevant behaviors. Using phosphoproteomic screening, we identified growth-associated signaling cascades dysregulated upon Dyrk1a deletion, including TrkB-BDNF (tyrosine receptor kinase B–brain-derived neurotrophic factor), an important regulator of ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) and mTOR (mammalian target of rapamycin) signaling. Genetic suppression of Pten or pharmacological treatment with IGF-1 (insulin-like growth factor-1), both of which impinge on these signaling cascades, rescued microcephaly and neuronal undergrowth in neonatal mutants. Altogether, these findings identify a previously unknown mechanism through which Dyrk1a mutations disrupt growth factor signaling in the developing brain, thus influencing neuronal growth and connectivity. Our results place DYRK1A as a critical regulator of a biological pathway known to be dysregulated in humans with autism spectrum disorder and intellectual disability. In addition, these data position Dyrk1a within a larger group of autism spectrum disorder/intellectual disability risk genes that impinge on growth-associated signaling cascades to regulate brain size and connectivity, suggesting a point of convergence for multiple autism etiologies. [ABSTRACT FROM AUTHOR]

[Display omitted] Extracellular amyloid plaques made of Amyloid-β (Aβ) derived from amyloid precursor protein (APP) is one of the major neuropathological hallmarks of Alzheimer's disease (AD). There are three major isoforms of APP, APP 770 , APP 751 , and APP 695 generated by alternative splicing of exons 7 and 8. Exon 7 encodes the Kunitz protease inhibitor (KPI) domain. Its inclusion generates APP isoforms containing KPI, APP KPI+ , which is elevated in AD and Down syndrome (DS) brains and associated with increased Aβ deposition. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) phosphorylates many splicing factors and regulates the alternative splicing of pre-mRNA. It is upregulated in DS and AD brain. However, it is not yet clear whether Dyrk1A could regulate APP alternative splicing. In the present study, we overexpressed or knocked down Dyrk1A in cultured cells and observed that Dyrk1A promoted the inclusion of both APP exons 7 and 8. Moreover, a significant increase in APP exon7 inclusion was also detected in the forebrain and hippocampus of human Dyrk1A transgenic mice – Tg/Dyrk1A. Screening for splicing factors regulated by Dyrk1A revealed that serine/arginine-rich protein 9G8 inhibited APP exon7 inclusion and interacted with APP pre-mRNA. In vitro , expression of exon 7 facilitated APP cleavage. In human Dyrk1A transgenic mice, we also found an increase in Aβ production. These findings suggest that Dyrk1A inhibits the splicing factor 9G8 and promotes APP exon 7 inclusion, leading to more APP KPI+ expression and APP cleavage and potentially contributing to Aβ production in vivo. [ABSTRACT FROM AUTHOR]

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) plays an essential role in Tau and Aβ pathology closely related to Alzheimer's disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitor for clinical use as anti-AD therapy. This is somewhat due to the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried out in silico screening, in vitro assays and in vivo efficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. By in silico screening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compound Q17 (Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compound Q17 and two amino acid residues named GLU239 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compound Q17 could protect the SH-SY5Y human neuroblastoma cell line from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compound Q17 significantly improved cognitive dysfunction of 3 × Tg-AD mice, ameliorated pathological changes, and attenuated Tau hyperphosphorylation as well as Aβ deposition. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compound Q17 in this study is worthy of further study. Graphic abstract [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer’s disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.