DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective

Pathak, Ankita; Rohilla, A.; Gupta, Tanya; Akhtar, Md. Jawaid; Haider, Rafi; Sharma, Kalicharan; Haider, Kashif; Yar, Mohammad Shahar

doi:10.1016/j.ejmech.2018.08.093

Cited by 38 publications

(34 citation statements)

References 93 publications

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“…By contrast, inactivating mutations in just one DYRK1A allele (gene truncation, small deletions and insertions, or nonsense mutations) are responsible for a rare syndrome known as DYRK1A haploinsufficiency (OMIM: 614104; ORPHA: 464306), characterized by a general developmental delay, microcephaly, seizures and a characteristic facial gestalt 11 . Moreover, deregulation of the DYRK1A gene could also be involved in other human pathologies, such as neurodegenerative diseases, diabetes, osteoporosis or cardiac dysfunction 12–15 , and recent evidence points to a role for DYRK1A in the progression of several types of cancer 16–20 . However, the role of DYRK1A as a negative or positive effector of tumor progression could be complex and tumor cell-dependent.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response

Roewenstrunk

Vona

Chen

et al. 2019

Sci Rep

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Dysregulation of the DYRK1A protein kinase has been associated with human disease. On the one hand, its overexpression in trisomy 21 has been linked to certain pathological traits of Down syndrome, while on the other, inactivating mutations in just one allele are responsible for a distinct yet rare clinical syndrome, DYRK1A haploinsufficiency. Moreover, altered expression of this kinase may also provoke other human pathologies, including cancer and diabetes. Although a few DYRK1A substrates have been described, its upstream regulators and downstream targets are still poorly understood, an information that could shed light on the functions of DYRK1A in the cell. Here, we carried out a proteomic screen using antibody-based affinity purification coupled to mass spectrometry to identify proteins that directly or indirectly bind to endogenous DYRK1A. We show that the use of a cell line not expressing DYRK1A, generated by CRISPR/Cas9 technology, was needed in order to discriminate between true positives and non-specific interactions. Most of the proteins identified in the screen are novel candidate DYRK1A interactors linked to a variety of activities in the cell. The in-depth characterization of DYRK1A’s functional interaction with one of them, the E3 ubiquitin ligase RNF169, revealed a role for this kinase in the DNA damage response. We found that RNF169 is a DYRK1A substrate and we identified several of its phosphorylation sites. In particular, one of these sites appears to modify the ability of RNF169 to displace 53BP1 from sites of DNA damage. Indeed, DYRK1A depletion increases cell sensitivity to ionizing irradiation. Therefore, our unbiased proteomic screen has revealed a novel activity of DYRK1A, expanding the complex role of this kinase in controlling cell homeostasis.

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Section: Introductionmentioning

confidence: 99%

A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response

Roewenstrunk

Vona

Chen

et al. 2019

Sci Rep

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“…DYRK1A and RCAN1 overexpression result in tau hyperphosphorylation, suggesting that these two proteins participate in the formation of the neurofibrillary tangles that are the other hallmark of AD (Ryoo et al, 2008, Wegiel et al, 2011. Moreover, DYRK1A overexpression has been proposed to phosphorylate APP, facilitating APP cleavage by BACE1 and the γ-secretase processing into Aβ40 and Aβ42 (Ryoo et al, 2008, Lee et al, 2003, Vingtdeux et al, 2005, Pathak et al, 2018, García-Cerro et al, 2017. A cooperative interaction has been revealed between DYRK1A and RCAN1 on transcriptional activity via the suppression of the activity of the transcription factor NFAT and resulting in a delay of neuron production during corticogenesis (Kurabayashi and Sanada, 2013).…”

Section: Iii22 More Than the Dscrmentioning

confidence: 99%

Modeling Down syndrome in animals from the early stage to the 4.0 models and next

Moreno

Brault

Birling

et al. 2020

Progress in Brain Research

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Short Abstract (<200 words)The genotype-phenotype relationship and the physiopathology of Down Syndrome (DS) have been explored in the last twenty years with more and more relevant mouse models. From the early age of transgenesis to the new CRISPR/CAS9-derived chromosomal engineering and the transchromosomic technologies, mouse models have been key to identify homologous genes or entire regions homologous to the human chromosome 21 that are necessary or sufficient to induce DS features, to investigate the complexity of the genetic interactions that are involved in DS and to explore therapeutic strategies. In this review we report the new developments made, how genomic data and new genetic tools have deeply changed our way of making models, extended our panel of animal models, and increased our understanding of the neurobiology of the disease. But even if we have made an incredible progress which promises to make DS a curable condition, we are facing new research challenges to nurture our knowledge of DS pathophysiology as a neurodevelopmental disorder with many comorbidities during ageing. Keyword listGenome, animal models, transgenesis, chromosomal engineering, transchromosomic, behaviour and cognition, neurobiology of disease.

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“…In addition, as discussed above in the Introduction, several other gene targets on Hsa21 have been shown to affect Tau phosphorylation, both in vivo and in vitro. These include RCAN1 (Jung et al, ), APP (Hartley et al, ), and DYRK1A (Jung et al, ; Pathak et al, ; Ryoo et al, ), which are all overexpressed in DS mouse models and humans with DS. Further studies are warranted to examine the effects of these overexpressed genes, gene interactions between them, as well as other gene targets, on Hsa21, and their role for exosome formation or secretion as well as spreading of toxic agents between brain regions and between cell types or individuals.…”

Section: Exosomal Cargomentioning

confidence: 99%

“…In fact, overexpression of DYRK1A results in altered cognitive abilities, defective cortical microarchitecture, and imbalance of cortical excitation/inhibition, as evidenced by decreased excitability and deficits in gamma frequency in the prefrontal cortex (Ruiz‐Mejias et al, ). DYRK1A also causes phosphorylation of APP, which leads to its cleavage in Aβ 40 and Aβ 42 , playing a critical role in the early onset of AD pathologies in DS (Pathak et al, ). This effect of DYRK1A may be especially detrimental in people with DS, because the APP gene is located on Hsa21 (see above and Glasson, Dye, & Bittles, ), leading to an overexpression of APP, and the formation of toxic amyloid peptides early in life (Schoeppe et al, ).…”

Section: Introductionmentioning

confidence: 99%

Exosome release and cargo in Down syndrome

Hamlett

LaRosa

Mufson

et al. 2019

Developmental Neurobiology

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Down syndrome (DS) is a multisystem disorder affecting 1 in 800 births worldwide. Advancing technology, medical treatment, and social intervention have dramatically increased life expectancy, yet there are many etiologies of this disorder that are in need of further research. The advent of the ability to capture extracellular vesicles (EVs) in blood from specific cell types allows for the investigation of novel intracellular processes. Exosomes are one type of EVs that have demonstrated great potential in uncovering new biomarkers of neurodegeneration and disease, and also that appear to be intricately involved in the transsynaptic spread of pathogenic factors underlying Alzheimer's disease and other neurological diseases. Exosomes are nanosized vesicles, generated in endosomal multivesicular bodies (MVBs) and secreted by most cells in the body. Since exosomes are important mediators of intercellular communication and genetic exchange, they have emerged as a major research focus and have revealed novel biological sequelae involved in conditions afflicting the DS population. This review summarizes current knowledge on exosome biology in individuals with DS, both early in life and in aging individuals. Collectively these studies have demonstrated that complex multicellular processes underlying DS etiologies may include abnormal formation and secretion of extracellular vesicles such as exosomes.

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DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective

Cited by 38 publications

References 93 publications

A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response

A comprehensive proteomics-based interaction screen that links DYRK1A to RNF169 and to the DNA damage response

Modeling Down syndrome in animals from the early stage to the 4.0 models and next

Exosome release and cargo in Down syndrome

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