Dyrk1a from Gene Function in Development and Physiology to Dosage Correction across Life Span in Down Syndrome

Down syndrome is the main cause of intellectual disabilities with a large set of comorbidities from developmental origins but also that appeared across life span. Investigation of the genetic overdosage found in Down syndrome, due to the trisomy of human chromosome 21, has pointed to one main driver gene, the Dual-specificity tyrosine-regulated kinase 1A (Dyrk1a). Dyrk1a is a murine homolog of the drosophila minibrain gene. It has been found to be involved in many biological processes during development and in adulthood. Further analysis showed its haploinsufficiency in mental retardation disease 7 and its involvement in Alzheimer’s disease. DYRK1A plays a role in major developmental steps of brain development, controlling the proliferation of neural progenitors, the migration of neurons, their dendritogenesis and the function of the synapse. Several strategies targeting the overdosage of DYRK1A in DS with specific kinase inhibitors have showed promising evidence that DS cognitive conditions can be alleviated. Nevertheless, providing conditions for proper temporal treatment and to tackle the neurodevelopmental and the neurodegenerative aspects of DS across life span is still an open question.

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Cbs overdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically with Dyrk1a

Human Molecular Genetics ◽

10.1093/hmg/ddy447 ◽

2019 ◽

Vol 28 (9) ◽

pp. 1561-1577 ◽

Cited By ~ 7

Author(s):

Damien Marechal ◽

Véronique Brault ◽

Alice Leon ◽

Dehren Martin ◽

Patricia Lopes Pereira ◽

...

Keyword(s):

Down Syndrome ◽

Chromosome 21 ◽

Pharmacological Intervention ◽

The Novel ◽

Cystathionine Beta Synthase ◽

Human Chromosome 21 ◽

Dual Specificity ◽

Intervention Point ◽

Intellectual Deficiencies ◽

Necessary And Sufficient

Abstract Identifying dosage-sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) shows cognitive phenotypes that need to be investigated to identify the main genetic driver. Here, we report that three copies of the cystathionine-beta-synthase gene (Cbs) in the Dp1Yah mice are necessary to observe a deficit in the novel object recognition (NOR) paradigm. Moreover, the overexpression of Cbs alone is sufficient to induce deficits in the NOR test. Accordingly, overexpressing human CBS specifically in Camk2a-expressing neurons leads to impaired objects discrimination. Altogether, this shows that Cbs overdosage is involved in DS learning and memory phenotypes. To go further, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast. Pharmacological intervention in Tg(CBS) mice with one selected compound restored memory in the NOR test. In addition, using a genetic approach, we demonstrated an epistatic interaction between Cbs and Dyrk1a, another human chromosome 21-located gene (which encodes the dual-specificity tyrosine phosphorylation-regulated kinase 1a) and an already known target for DS therapeutic intervention. Further analysis using proteomic approaches highlighted several molecular pathways, including synaptic transmission, cell projection morphogenesis and actin cytoskeleton, that are affected by DYRK1A and CBS overexpression. Overall, we demonstrated that CBS overdosage underpins the DS-related recognition memory deficit and that both CBS and DYRK1A interact to control accurate memory processes in DS. In addition, our study establishes CBS as an intervention point for treating intellectual deficiencies linked to DS.

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DYRK1A Enhances the Mitogen-activated Protein Kinase Cascade in PC12 Cells by Forming a Complex with Ras, B-Raf, and MEK1

Molecular Biology of the Cell ◽

10.1091/mbc.e04-12-1085 ◽

2005 ◽

Vol 16 (8) ◽

pp. 3562-3573 ◽

Cited By ~ 51

Author(s):

Paul A. Kelly ◽

Zohra Rahmani

Keyword(s):

Down Syndrome ◽

Neuronal Differentiation ◽

Critical Role ◽

Chromosome 21 ◽

Mitogen Activated Protein Kinase ◽

Serine Threonine Kinase ◽

Erk Activation ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Kinase Cascade

Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) is the human homologue of the Drosophila mnb (minibrain) gene. In Drosophila, mnb is involved in postembryonic neurogenesis. In human, DYRK1A maps within the Down syndrome critical region of chromosome 21 and is overexpressed in Down syndrome embryonic brain. Despite its potential involvement in the neurobiological alterations observed in Down syndrome patients, the biological functions of the serine/threonine kinase DYRK1A have not been identified yet. Here, we report that DYRK1A overexpression potentiates nerve growth factor (NGF)-mediated PC12 neuronal differentiation by up-regulating the Ras/MAP kinase signaling pathway independently of its kinase activity. Furthermore, we show that DYRK1A prolongs the kinetics of ERK activation by interacting with Ras, B-Raf, and MEK1 to facilitate the formation of a Ras/B-Raf/MEK1 multiprotein complex. These data indicate that DYRK1A may play a critical role in Ras-dependent transducing signals that are required for promoting or maintaining neuronal differentiation and suggest that overexpression of DYRK1A may contribute to the neurological abnormalities observed in Down syndrome patients.

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Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1704143114 ◽

2017 ◽

Vol 114 (38) ◽

pp. 10268-10273 ◽

Cited By ~ 33

Author(s):

Akiko Nakano-Kobayashi ◽

Tomonari Awaya ◽

Isao Kii ◽

Yuto Sumida ◽

Yukiko Okuno ◽

...

Keyword(s):

Down Syndrome ◽

Structure And Function ◽

Chromosome 21 ◽

Murine Models ◽

Dual Specificity ◽

Brain Structure And Function ◽

Newborn Neurons ◽

And Function ◽

Abnormal Behaviors ◽

Potent Inhibitory Activity

Down syndrome (DS) caused by trisomy of chromosome 21 is the most common genetic cause of intellectual disability. Although the prenatal diagnosis of DS has become feasible, there are no therapies available for the rescue of DS-related neurocognitive impairment. A growth inducer newly identified in our screen of neural stem cells (NSCs) has potent inhibitory activity against dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and was found to rescue proliferative deficits in Ts65Dn-derived neurospheres and human NSCs derived from individuals with DS. The oral administration of this compound, named ALGERNON (altered generation of neurons), restored NSC proliferation in murine models of DS and increased the number of newborn neurons. Moreover, administration of ALGERNON to pregnant dams rescued aberrant cortical formation in DS mouse embryos and prevented the development of abnormal behaviors in DS offspring. These data suggest that the neurogenic phenotype of DS can be prevented by ALGERNON prenatal therapy.

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Down Syndrome Research Expedited by Decoding of Human Chromosome 21: Second Human Chromosome Sequenced by the Human Genome Project

PsycEXTRA Dataset ◽

10.1037/e634112007-001 ◽

2000 ◽

Keyword(s):

Down Syndrome ◽

Human Chromosome ◽

Human Genome ◽

Human Genome Project ◽

Genome Project ◽

Chromosome 21 ◽

Human Chromosome 21 ◽

The Human Genome Project

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Faculty Opinions recommendation of A chromosome 21 critical region does not cause specific Down syndrome phenotypes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1022241.251789 ◽

2004 ◽

Author(s):

Yasushi Okazaki

Keyword(s):

Down Syndrome ◽

Critical Region ◽

Chromosome 21

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Faculty Opinions recommendation of Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090195.543413 ◽

2007 ◽

Author(s):

Giovanni Neri

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Human Chromosome ◽

Chromosome 21 ◽

Disease Phenotypes ◽

Human Chromosome 21

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Characterization of Caenorhabditis elegans Homologs of the Down Syndrome Candidate Gene DYRK1A

Genetics ◽

10.1093/genetics/163.2.571 ◽

2003 ◽

Vol 163 (2) ◽

pp. 571-580 ◽

Cited By ~ 1

Author(s):

William B Raich ◽

Celine Moorman ◽

Clay O Lacefield ◽

Jonah Lehrer ◽

Dusan Bartsch ◽

...

Keyword(s):

Down Syndrome ◽

Caenorhabditis Elegans ◽

Trisomy 21 ◽

Gene Dosage ◽

Inducible Promoters ◽

C Elegans ◽

Dual Specificity ◽

Specificity Protein

Abstract The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified three DYRK/minibrain-like genes in the genome sequence of Caenorhabditis elegans, termed mbk-1, mbk-2, and hpk-1. We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss of mbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene, mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of its C. elegans ortholog mbk-1. We found that animals containing additional copies of the mbk-1 gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates with mbk-1 gene dosage. Using tissue-specific and inducible promoters, we show that additional copies of mbk-1 can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.

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Cytogenetic, Molecular and FISH Analysis of an Isodicentric Chromosome 21 idic(21)(q22.3) in a Mildly-Affected Patient with Down Syndrome

International Journal of Human Genetics ◽

10.1080/09723757.2007.11885998 ◽

2007 ◽

Vol 7 (3) ◽

pp. 215-218 ◽

Cited By ~ 3

Author(s):

Frenny J Sheth ◽

Uppala Radhakrishna ◽

Michael A Morris ◽

Jean-Louis Blouin ◽

Jayesh J Sheth ◽

...

Keyword(s):

Down Syndrome ◽

Chromosome 21 ◽

Fish Analysis ◽

Affected Patient ◽

Isodicentric Chromosome

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A prenatal diagnosis case of partial duplication 21q21.1-q21.2 with normal phenotype maternally inherited

BMC Medical Genomics ◽

10.1186/s12920-021-01013-x ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Chunyan Jin ◽

Zhiping Gu ◽

Xiaohan Jiang ◽

Pei Yu ◽

Tianhui Xu

Keyword(s):

Down Syndrome ◽

Pregnant Woman ◽

Prenatal Testing ◽

Chromosome 21 ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Serological Screening ◽

Partial Duplication ◽

Her Family ◽

Clinical Consequences

Abstract Background Down syndrome is characterized by trisomy 21 or partial duplication of chromosome 21. Extensive studies have focused on the identification of the Down Syndrome Critical Region (DSCR). We aim to provide evidence that duplication of 21q21.1-q21.2 should not be included in the DSCR and it has no clinical consequences on the phenotype. Case presentation Because serological screening was not performed at the appropriate gestational age, noninvasive prenatal testing (NIPT) analysis was performed for a pregnant woman with normal prenatal examinations at 22 weeks of gestation. The NIPT results revealed a 5.8 Mb maternally inherited duplication of 21q21.1-q21.2. To assess whether the fetus also carried this duplication, ultrasound-guided amniocentesis was conducted, and the result of chromosomal microarray analysis (CMA) with amniotic fluid showed a 6.7 Mb duplication of 21q21.1-q21.2 (ranging from position 18,981,715 to 25,707,009). This partial duplication of 21q21.1-q21.2 in the fetus was maternally inherited. After genetic counseling, the pregnant woman and her family decided to continue the pregnancy. Conclusion Our case clearly indicates that 21q21.1-q21.2 duplication is not included in the DSCR and most likely has no clinical consequences on phenotype.

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Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

Biomolecules ◽

10.3390/biom11020266 ◽

2021 ◽

Vol 11 (2) ◽

pp. 266

Author(s):

Chiara Lanzillotta ◽

Fabio Di Domenico

Keyword(s):

Down Syndrome ◽

Stress Response ◽

Stress Responses ◽

Redox Balance ◽

Antioxidant Response ◽

Chromosome 21 ◽

Therapeutic Approaches ◽

Genomic Disorder ◽

Therapeutic Molecules ◽

Early Alzheimer’S Disease

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.

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