Skeletal dynamics of Down syndrome: A developing perspective.
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ABSTRACT:
SUBMITTER: LaCombe JM
PROVIDER: S-EPMC7044033 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early-onset Alzheimer's disease (AD)-type dementia by early midlife. Despite ongoing clinical trials to treat late-onset AD, individuals with DS are often excluded. Furthermore, timely diagnosis or management is often not available. Of the genetic causes of AD, people with DS represent the largest cohort. Currently, there is a knowledge gap regarding the underlying neurobiological mechanisms of DS-related AD (DS-AD), partly due to limited access to well-characterized brain tissue and biomaterials for research. To address this challenge, we created an international consortium of brain banks focused on collecting and disseminating brain tissue from persons with DS throughout their lifespan, named the Down Syndrome Biobank Consortium (DSBC) consisting of 11 biobanking sites located in Europe, India, and the USA. This perspective describes the DSBC harmonized protocols and tissue dissemination goals.
| S-EPMC10984425 | biostudies-literature
Project description:Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11 times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.
| S-EPMC4990229 | biostudies-literature
Project description:Trisomy 21 (T21), known as Down syndrome (DS), is a widely studied chromosomal abnormality. Previous studies have shown that DS individuals have a unique cancer profile. While exhibiting low solid tumor prevalence, DS patients are at risk for hematologic cancers, such as acute megakaryocytic leukemia and acute lymphoblastic leukemia. We speculated that endothelial cells are active players in this clinical background. To this end, we hypothesized that impaired DS endothelial development and functionality, impacted by genome-wide T21 alterations, potentially results in a suboptimal endothelial microenvironment with the capability to prevent solid tumor growth. To test this hypothesis, we assessed molecular and phenotypic differences of endothelial cells differentiated from Down syndrome and euploid iPS cells. Microarray, RNA-Seq, and bioinformatic analyses revealed that most significantly expressed genes belong to angiogenic, cytoskeletal rearrangement, extracellular matrix remodeling, and inflammatory pathways. Interestingly, the majority of these genes are not located on Chromosome 21. To substantiate these findings, we carried out functional assays. The obtained phenotypic results correlated with the molecular data and showed that Down syndrome endothelial cells exhibit decreased proliferation, reduced migration, and a weak TNF-α inflammatory response. Based on this data, we provide a set of genes potentially associated with Down syndrome's elevated leukemic incidence and its unfavorable solid tumor microenvironment-highlighting the potential use of these genes as therapeutic targets in translational cancer research.
| S-EPMC7486695 | biostudies-literature
Project description:Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). Abilities relating to executive function, memory and language are particularly affected in DS, although there is a large variability across individuals. People with DS also show an increased risk of developing dementia. While assessment batteries have been developed for adults with DS to assess cognitive abilities, these batteries may not be suitable for those with more severe IDs, dementia, or visual / hearing difficulties. Here we report the development of an informant rated questionnaire, the Cognitive Scale for Down Syndrome (CS-DS), which focuses on everyday abilities relating to executive function, memory and language, and is suitable for assessing these abilities in all adults with DS regardless of cognitive ability. Complete questionnaires were collected about 128 individuals with DS. After final question selection we found high internal consistency scores across the total questionnaire and within the executive function, memory and language domains. CS-DS scores showed a wide range, with minimal floor and ceiling effects. We found high interrater (n = 55) and test retest (n = 36) intraclass correlations. CS-DS scores were significantly lower in those aged 41+ with significant cognitive decline compared to those without decline. Across all adults without cognitive decline, CS-DS scores correlated significantly to measures of general abilities. Exploratory factor analysis suggested five factors within the scale, relating to memory, self-regulation / inhibition, self-direction / initiation, communication, and focussing attention. The CS-DS therefore shows good interrater and test retest reliability, and appears to be a valid and suitable informant rating tool for assessing everyday cognitive abilities in a wide range of individuals with DS. Such a questionnaire may be a useful outcome measure for intervention studies to assess improvements to cognition, in addition to detecting dementia-related cognitive decline. The CS-DS may also be a useful tool for other populations with ID.
| S-EPMC4859552 | biostudies-literature
Project description:Using Illumina 450K arrays, 1.85% of analyzed CpG sites were hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the γ-protocadherin (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Dysregulation of CPT1B and NOX5 may be associated with mitochondrial dysfunction and increased cell damage in the developing DS brain. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.
2016-08-03 | GSE73747 | GEO
Project description:Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may serve as a useful model to examine potential factors responsible for DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of unfatigued Ts65Dn soleus, but a 12% reduction in force was observed in Ts65Dn muscle during recovery following fatiguing contractions compared to WT muscle (p<0.05). Oxidative stress may contribute to DS-related pathologies, including muscle weakness, which may be the result of overexpression of chromosome 21 genes (e.g., copper-zinc superoxide dismutase (SOD1)). SOD1 expression was 25% higher (p<0.05) in Ts65Dn soleus compared to WT muscle but levels of other antioxidant proteins were unchanged. Lipid peroxidation (4-hydroxynoneal) was unaltered in Ts65Dn muscle although protein carbonyls were 20% greater compared to muscle of WT animals (p<0.05). Cytochrome c oxidase expression was reduced 22% in Ts65Dn muscle, suggesting a limitation in mitochondrial function may contribute to post-fatigue muscle weakness. Microarray analysis of Ts65Dn soleus revealed alteration of numerous cellular pathways including: proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, the Ts65Dn mouse displays evidence of muscle dysfunction, and the potential role of mitochondria and oxidative stress warrants further investigation.
2013-01-06 | GSE39159 | GEO
Project description:Harnessing the potential of human stem cells for modeling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. We show that human induced pluripotent stem cell (iPSC)-derived cortical neurons transplanted into the adult mouse cortex consistently organized into large (up to ~100 mm3) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Lastly, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modeling of cortical development, physiology, and pathogenesis.
| S-EPMC6570619 | biostudies-literature
Project description:Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may serve as a useful model to examine potential factors responsible for DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of unfatigued Ts65Dn soleus, but a 12% reduction in force was observed in Ts65Dn muscle during recovery following fatiguing contractions compared to WT muscle (p<0.05). Oxidative stress may contribute to DS-related pathologies, including muscle weakness, which may be the result of overexpression of chromosome 21 genes (e.g., copper-zinc superoxide dismutase (SOD1)). SOD1 expression was 25% higher (p<0.05) in Ts65Dn soleus compared to WT muscle but levels of other antioxidant proteins were unchanged. Lipid peroxidation (4-hydroxynoneal) was unaltered in Ts65Dn muscle although protein carbonyls were 20% greater compared to muscle of WT animals (p<0.05). Cytochrome c oxidase expression was reduced 22% in Ts65Dn muscle, suggesting a limitation in mitochondrial function may contribute to post-fatigue muscle weakness. Microarray analysis of Ts65Dn soleus revealed alteration of numerous cellular pathways including: proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, the Ts65Dn mouse displays evidence of muscle dysfunction, and the potential role of mitochondria and oxidative stress warrants further investigation. We used microarrays to gain insight into potential mechanisms of DS-associated skeletal muscle weakness. Soleus muscles were obtained from four male Ts65Dn (DS) mice and four male colony control mice. Animals were apparently healthy and approximately five months old. The muscles were harvested in the basal state under anesthesia induced by sodium pentobarbital at approximately the same time of the day.
2013-01-06 | E-GEOD-39159 | biostudies-arrayexpress
Project description:The emergence of resting-state functional connectivity (rsFC) analysis, which examines temporal correlations of low-frequency (<0.1 Hz) blood oxygen level-dependent signal fluctuations between brain regions, has dramatically improved our understanding of the functional architecture of the typically developing (TD) human brain. This study examined rsFC in Down syndrome (DS) compared with another neurodevelopmental disorder, Williams syndrome (WS), and TD. Ten subjects with DS, 18 subjects with WS, and 40 subjects with TD each participated in a 3-Tesla MRI scan. We tested for group differences (DS vs. TD, DS vs. WS, and WS vs. TD) in between- and within-network rsFC connectivity for seven functional networks. For the DS group, we also examined associations between rsFC and other cognitive and genetic risk factors. In DS compared with TD, we observed higher levels of between-network connectivity in 6 out 21 network pairs but no differences in within-network connectivity. Participants with WS showed lower levels of within-network connectivity and no significant differences in between-network connectivity relative to DS. Finally, our comparison between WS and TD controls revealed lower within-network connectivity in multiple networks and higher between-network connectivity in one network pair relative to TD controls. While preliminary due to modest sample sizes, our findings suggest a global difference in between-network connectivity in individuals with neurodevelopmental disorders compared with controls and that such a difference is exacerbated across many brain regions in DS. However, this alteration in DS does not appear to extend to within-network connections, and therefore, the altered between-network connectivity must be interpreted within the framework of an intact intra-network pattern of activity. In contrast, WS shows markedly lower levels of within-network connectivity in the default mode network and somatomotor network relative to controls. These findings warrant further investigation using a task-based procedure that may help disentangle the relationship between brain function and cognitive performance across the spectrum of neurodevelopmental disorders.
| S-EPMC4601631 | biostudies-literature