Changing Paradigms in Down Syndrome: The First International Conference of the Trisomy 21 Research Society

Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) in humans with an incidence of ∼1:1,000 live births worldwide. It is caused by the presence of an extra copy of all or a segment of the long arm of human chromosome 21 (trisomy 21). People with DS present with a constellation of phenotypic alterations involving most organs and organ systems. ID is present in all people with DS, albeit with variable severity. DS is also the most frequent genetic cause of Alzheimer's disease (AD), and ∼50% of those with DS will develop AD-related dementia. In the last few years, significant progress has been made in understanding the crucial genotype-phenotype relationships in DS, in identifying the alterations in molecular pathways leading to the various clinical conditions present in DS, and in preclinical evaluations of potential therapies to improve the overall health and well-being of individuals with DS. In June 2015, 230 scientists, advocates, patients, and family members met in Paris for the 1st International Conference of the Trisomy 21 Research Society. Here, we report some of the most relevant presentations that took place during the meeting

Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A

Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) — a member of a natural polyphenols family, found in great amount in green tea leaves — is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice

Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6–9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer’s disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar­ma­cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21

The power of comparative and developmental studies for mouse models of Down syndrome

Since the genetic basis for Down syndrome (DS) was described, understanding the causative relationship between genes at dosage imbalance and phenotypes associated with DS has been a principal goal of researchers studying trisomy 21 (Ts21). Though inferences to the gene-phenotype relationship in humans have been made, evidence linking a specific gene or region to a particular congenital phenotype has been limited. To further understand the genetic basis for DS phenotypes, mouse models with three copies of human chromosome 21 (Hsa21) orthologs have been developed. Mouse models offer access to every tissue at each stage of development, opportunity to manipulate genetic content, and ability to precisely quantify phenotypes. Numerous approaches to recreate trisomic composition and analyze phenotypes similar to DS have resulted in diverse trisomic mouse models. A murine intraspecies comparative analysis of different genetic models of Ts21 and specific DS phenotypes reveals the complexity of trisomy and important considerations to understand the etiology of and strategies for amelioration or prevention of trisomic phenotypes. By analyzing individual phenotypes in different mouse models throughout development, such as neurologic, craniofacial, and cardiovascular abnormalities, greater insight into the gene-phenotype relationship has been demonstrated. In this review we discuss how phenotype-based comparisons between DS mouse models have been useful in analyzing the relationship of trisomy and DS phenotypes

The Volatile Anesthetic Isoflurane Increases Endothelial Adenosine Generation via Microparticle Ecto-5′-Nucleotidase (CD73) Release

Endothelial dysfunction is common in acute and chronic organ injury. Isoflurane is a widely used halogenated volatile anesthetic during the perioperative period and protects against endothelial cell death and inflammation. In this study, we tested whether isoflurane induces endothelial ecto-5′-nucleotidase (CD73) and cytoprotective adenosine generation to protect against endothelial cell injury. Clinically relevant concentrations of isoflurane induced CD73 activity and increased adenosine generation in cultured human umbilical vein or mouse glomerular endothelial cells. Surprisingly, isoflurane-mediated induction of endothelial CD73 activity occurred within 1 hr and without synthesizing new CD73. We determined that isoflurane rapidly increased CD73 containing endothelial microparticles into the cell culture media. Indeed, microparticles isolated from isoflurane-treated endothelial cells had significantly higher CD73 activity as well as increased CD73 protein. In vivo, plasma from mice anesthetized with isoflurane had significantly higher endothelial cell-derived CD144+ CD73+ microparticles and had increased microparticle CD73 activity compared to plasma from pentobarbital-anesthetized mice. Supporting a critical role of CD73 in isoflurane-mediated endothelial protection, a selective CD73 inhibitor (APCP) prevented isoflurane-induced protection against human endothelial cell inflammation and apoptosis. In addition, isoflurane activated endothelial cells Rho kinase evidenced by myosin phosphatase target subunit-1 and myosin light chain phosphorylation. Furthermore, isoflurane-induced release of CD73 containing microparticles was significantly attenuated by a selective Rho kinase inhibitor (Y27632). Taken together, we conclude that the volatile anesthetic isoflurane causes Rho kinase-mediated release of endothelial microparticles containing preformed CD73 and increase adenosine generation to protect against endothelial apoptosis and inflammation

Phosphorylation by Dyrk1A of Clathrin Coated Vesicle-Associated Proteins: Identification of the Substrate Proteins and the Effects of Phosphorylation

Dyrk1A phosphorylated multiple proteins in the clathrin-coated vesicle (CCV) preparations obtained from rat brains. Mass spectrometric analysis identified MAP1A, MAP2, AP180, and α- and β-adaptins as the phosphorylated proteins in the CCVs. Each protein was subsequently confirmed by [32P]-labeling and immunological methods. The Dyrk1A-mediated phosphorylation released the majority of MAP1A and MAP2 and enhanced the release of AP180 and adaptin subunits from the CCVs. Furthermore, Dyrk1A displaced adaptor proteins physically from CCVs in a kinase-concentration dependent manner. The clathrin heavy chain release rate, in contrast, was not affected by Dyrk1A. Surprisingly, the Dyrk1A-mediated phosphorylation of α- and β-adaptins led to dissociation of the AP2 complex, and released only β-adaptin from the CCVs. AP180 was phosphorylated by Dyrk1A also in the membrane-free fractions, but α- and β-adaptins were not. Dyrk1A was detected in the isolated CCVs and was co-localized with clathrin in neurons from mouse brain sections and from primary cultured rat hippocampus. Previously, we proposed that Dyrk1A inhibits the onset of clathrin-mediated endocytosis in neurons by phosphorylating dynamin 1, amphiphysin 1, and synaptojanin 1. Current results suggest that besides the inhibition, Dyrk1A promotes the uncoating process of endocytosed CCVs

Cell type-specific over-expression of chromosome 21 genes in fibroblasts and fetal hearts with trisomy 21

BACKGROUND: Down syndrome (DS) is caused by trisomy 21 (+21), but the aberrations in gene expression resulting from this chromosomal aneuploidy are not yet completely understood. METHODS: We used oligonucleotide microarrays to survey mRNA expression in early- and late-passage control and +21 fibroblasts and mid-gestation fetal hearts. We supplemented this analysis with northern blotting, western blotting, real-time RT-PCR, and immunohistochemistry. RESULTS: We found chromosome 21 genes consistently over-represented among the genes over-expressed in the +21 samples. However, these sets of over-expressed genes differed across the three cell/tissue types. The chromosome 21 gene MX1 was strongly over-expressed (mean 16-fold) in senescent +21 fibroblasts, a result verified by northern and western blotting. MX1 is an interferon target gene, and its mRNA was induced by interferons present in +21 fibroblast conditioned medium, suggesting an autocrine loop for its over-expression. By immunohistochemistry the p78(MX1 )protein was induced in lesional tissue of alopecia areata, an autoimmune disorder associated with DS. We found strong over-expression of the purine biosynthesis gene GART (mean 3-fold) in fetal hearts with +21 and verified this result by northern blotting and real-time RT-PCR. CONCLUSION: Different subsets of chromosome 21 genes are over-expressed in different cell types with +21, and for some genes this over-expression is non-linear (>1.5X). Hyperactive interferon signaling is a candidate pathway for cell senescence and autoimmune disorders in DS, and abnormal purine metabolism should be investigated for a potential role in cardiac defects

Rodent models in Down syndrome research: impact and future opportunities.

Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets