Indiana University-Purdue University Indianapolis (IUPUI) / Using Heideggerian interpretive phenomenology, this study illuminates the lived experience of an adapted dance program for individuals with Down syndrome and their family members. The overall pattern from both dancers and family members was adapted dance: connecting mind, body and soul. The primary theme from dancer interpretations was expressing a mosaic of positive experiences, and the primary theme from family member interpretations was experiencing pride in their loved ones. The dance program provided dancers an opportunity to express their authentic self while experiencing moments of full embodiment in the connection of their mind, body and soul. While dancers experienced the connection of mind-body-soul, family members recognized the importance of this connection in their loved one. This research is instrumental in advocating for opportunities for individuals with Down syndrome to experience dance as a social, physical and intellectual activity that results in learning and increasing social interactions. The research findings from this study can support future initiatives for dance programs that may influence a population that has limited access to physical activity and dance. The study’s teaching strategies, dance activities, class procedures and sequences, and feedback techniques can be used by other professionals who teach individuals with intellectual disabilities.

Down syndrome (DS) is caused by triplication of human chromosome 21 (HSA21) and is the most common genetic form of intellectual disability. It is unknown precisely how triplication of HSA21 results in the intellectual disability, but it is thought that the global transcriptional dysregulation caused by trisomy 21 perturbs multiple aspects of neurodevelopment that cumulatively contribute to its etiology. While the characteristics associated with DS can arise from any of the genes triplicated on HSA21, in this work we focus on oligodendrocyte transcription factor 2 (OLIG2). The progeny of neural progenitor cells (NPCs) expressing OLIG2 are likely to be involved in many of the cellular changes underlying the intellectual disability in DS. To explore the fate of OLIG2+ neural progenitors, we took advantage of two distinct models of DS, the Ts65Dn mouse model and induced pluripotent stem cells (iPSCs) derived from individuals with DS. Our results from these two systems identified multiple perturbations in development in the cellular progeny of OLIG2+ NPCs. In Ts65Dn, we identified alterations in neurons and glia derived from the OLIG2 expressing progenitor domain in the ventral spinal cord. There were significant differences in the number of motor neurons and interneurons present in the trisomic lumbar spinal cord depending on age of the animal pointing both to a neurodevelopment and a neurodegeneration phenotype in the Ts65Dn mice. Of particular note, we identified changes in oligodendrocyte (OL) maturation in the trisomic mice that are dependent on spatial location and developmental origin. In the dorsal corticospinal tract, there were significantly fewer mature OLs in the trisomic mice, and in the lateral funiculus we observed the opposite phenotype with more mature OLs being present in the trisomic animals. We then transitioned our studies into iPSCs where we were able to pattern OLIG2+ NPCs to either a spinal cord-like or a brain-like identity and study the OL lineage that differentiated from each progenitor pool. Similar to the region-specific dysregulation found in the Ts65Dn spinal cord, we identified perturbations in trisomic OLs that were dependent on whether the NPCs had been patterned to a brain-like or spinal cord-like fate. In the spinal cord-like NPCs, there was no difference in the proportion of cells expressing either OLIG2 or NKX2.2, the two transcription factors whose co-expression is essential for OL differentiation. Conversely, in the brain-like NPCs, there was a significant increase in OLIG2+ cells in the trisomic culture and a decrease in NKX2.2 mRNA expression. We identified a sonic hedgehog (SHH) signaling based mechanism underlying these changes in OLIG2 and NKX2.2 expression in the brain-like NPCs and normalized the proportion of trisomic cells expressing the transcription factors to euploid levels by modulating the activity of the SHH pathway. Finally, we continued the differentiation of the brain-like and spinal cord-like NPCs to committed OL precursor cells (OPCs) and allowed them to mature. We identified an increase in OPC production in the spinal cord-like trisomic culture which was not present in the brain-like OPCs. Conversely, we identified a maturation deficit in the brain-like trisomic OLs that was not present in the spinal cord-like OPCs. These results underscore the importance of regional patterning in characterizing changes in cell differentiation and fate in DS. Together, the findings presented in this work contribute to the understanding of the cellular and molecular etiology of the intellectual disability in DS and in particular the contribution of cells differentiated from OLIG2+ progenitors.

Barros et al. (2018) suggested that individuals with a diagnosis of down syndrome (DS) and/or autism spectrum disorder (ASD) face challenges in acquiring adaptive daily living skills (ADLs). As a result, more intensive support may be required to acquire such skills and quality of life (QoL) may be impacted for those individuals and their parents/caregivers/legal guardians. The purpose of this study was to teach children with a diagnosis of down syndrome (DS) or autism spectrum disorder (ASD) oral hygiene skills, specifically toothbrushing, utilizing basic video modeling. Three children between the ages of four – 11 with a diagnosis of DS or ASD viewed video models portraying a similar age peer completing the toothbrushing task. A concurrent multiple baseline across participants design was used and independence in tooth brushing was monitored. Results suggested that utilizing basic video modeling can increase correct independent responding in tooth brushing. When taught ADLs, individuals with a diagnosis of DS or ASD may be able to increase independence in everyday life such as feeding, using the bathroom, or living independently. Furthermore, acquiring ADLs can increase the QoL for individuals with a diagnosis of DS or ASD and for the parents/caregivers/legal guardians of those individuals.

Down syndrome (DS) is caused by the triplication of chromosome 21, but science is still investigating the precise mechanisms by which this results in the various phenotypes, such as anatomical abnormalities, intellectual deficits, and early development of Alzheimer’s disease (AD). The global changes in transcriptional activity and the altered expression of genes not transcribed from chromosome 21 point to changes to the epigenetic landscape. One of the candidate genes for this global gene dysregulation is High Mobility Group Nucleosome Binding Domain 1 (HMGN1) which is triplicated in DS. While investigating DS-associated B-cell acute lymphoblastic leukemia (B-ALL), researchers found the triplication of HMGN1 alone led to many of the same transcriptional and phenotypic changes that marked DS-associated B-cells from a mouse model with all 31 genes orthologous to human chromosome 21 genes triplicated. Amongst the pathways most affected by triplication, enrichment was greatest for targets of the Polycomb Repressive Complex 2 (PRC2) and sites of the transcriptionally repressive mark it catalyzes, H3K27me3. HMGN1 instead, promotes transcriptional activation and its overexpression leads to a global increase in RNA transcript levels. Therefore, overexpression of HMGN1 in DS may cause an increase in transcriptional activity and prevent the silencing of genes normally silenced by PRC2, with downstream effects on neurogenesis and gliogenesis, abnormal cellular migration, and deviant developmental timing that result in known DS phenotypes. With this hypothesis, we first wanted to quantify the levels of acetylation versus methylation at H3K27 in trisomy 21 induced pluripotent stem (iPS) cell-derived cellular models: neural progenitor cells (NPCs) and cortical organoids and to determine if there are measurable differences between the genotypes. We found a decrease in H3K27me3 in 130-day-old organoids, but not in NPCs. No changes were detected in the levels of H3K27ac. With the high comorbidity between DS and AD, and changes to the epigenome found in both diseases, we wondered whether there were specific alterations at H3K27 in DS-AD. To determine this, we performed an analysis of human postmortem brain tissue from individuals with DS-AD, AD, and control and quantified H3K27me3 and H3K27ac marks. Our data indicated that there are marginally significant changes in H3K27me3 that are unique to DS-AD as compared to control and AD samples. Encouraged by this data, we next measured gene expression levels of specific PRC2 target genes increased in trisomy. Our goal was to identify the causative relationship between the increased expression of HMGN1 in trisomy and upregulation of specific PRC2 target genes with known brain-related functions. We found that enhanced expression of particular PRC2 target genes in trisomic cells could be normalized with the short-hairpin RNA (shRNA)-induced knockdown of HMGN1 expression in trisomic NPCs. This implicates HMGN1 overexpression in DS in the dysregulation and overexpression of particular genes involved in morphogenesis, neurogenesis, neuronal migration, apoptosis, and cell viability through the antagonism of the PRC2 activity. We provided novel evidence for a possible mechanism for the cellular, molecular, and transcriptomic changes originating from the triplication of HMGN1 that can potentially lead to DS-related phenotypes such as intellectual disability and AD-related pathology. Furthermore, our findings suggest a possible therapeutic avenue to mitigate these phenotypes by regulating HMGN1 expression. Taken together, our work is the first to causatively connect HMGN1-induced epigenetic changes to DS-related brain cell phenotypes and to point out to a potential approach for correcting them. .

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