Showing papers on "Chromosome 21 published in 2022"
TL;DR: In this paper , the deubiquitinase USP25, encoded on chromosome 21, was shown to promote β cleavage of APP and Aβ generation by reducing ubiquitination and lysosomal degradation of both APP and BACE1.
Abstract: Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer’s disease (AD), implicating key roles for chromosome 21–encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene–mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and Aβ generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.
11 citations
TL;DR: Ts66Yah as discussed by the authors is a mouse model generated by CRISPR/Cas9 without the genomic region unrelated to trisomy of human chromosome 21 on the minichromosome.
Abstract: ABSTRACT Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). The understanding of genotype–phenotype relationships, the identification of driver genes and various proofs of concept for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16, homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 from Pisd-ps2/Scaf8 to Pde10a, containing 46 genes not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CRISPR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures were changed, suggesting genetic interactions between the Mir155-Zbtb21 and Scaf8-Pde10a intervals. Thus, Ts66Yah mice have stronger construct and face validity than Ts65Dn mice for mimicking consequences of DS genetic overdosage. Furthermore, this study is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21. This article has an associated First Person interview with the first author of the paper.
10 citations
TL;DR: In this article , a research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step for those with Down syndrome.
Abstract: Those with Down syndrome (DS)—trisomy for chromosome 21—are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.
5 citations
TL;DR: The importance of investigating how mitochondrial and lysosomal dysfunction could eventually contribute to understanding impaired heart function and development in subjects with the Hsa21 trisomy is highlighted.
Abstract: Down syndrome (DS) is a genetic disorder caused by a trisomy of the human chromosome 21 (Hsa21). Overexpression of Hsa21 genes that encode proteins and non-coding RNAs (ncRNAs) can disrupt several cellular functions and biological processes, especially in the heart. Congenital heart defects (CHDs) are present in 45–50% of individuals with DS. Here, we describe the genetic background of this condition (Hsa21 and non-Hsa21 genes), including the role of ncRNAs, and the relevance of these new players in the study of the pathophysiology of DS heart diseases. Additionally, we discuss several distinct pathways in cardiomyocytes which help maintain a functional heart, but that might trigger hypertrophy and oxidative stress when altered. Moreover, we highlight the importance of investigating how mitochondrial and lysosomal dysfunction could eventually contribute to understanding impaired heart function and development in subjects with the Hsa21 trisomy. Altogether, this review focuses on the newest insights about the gene expression, molecular pathways, and organelle alterations involved in the cardiac phenotype of DS.
5 citations
TL;DR: In this article , the authors discuss evidence that multiple genes on chromosome 21 are associated with metabolic dysfunction in Down syndrome, leading to increased risk of Alzheimer disease (AD), presumably conferred through genetic predispositions arising from trisomy 21.
4 citations
TL;DR: In this paper , the authors found that postnatal development of DYRK1A expression is dysregulated in trisomic animals, and found significant overexpression of Dyrk1A in the hippocampus, cerebral cortex, and cerebellum at postnatal day (P) 15 in male but not female-Ts65Dn mice.
Abstract: The neurotypical spatiotemporal patterns of gene expression are disrupted in Down syndrome (DS) by trisomy of human chromosome 21 (Hsa21), resulting in altered behavioral development and brain circuitry. The Ts65Dn DS mouse model exhibits similar phenotypes to individuals with DS due to three copies of approximately one-half of the genes found on Hsa21. Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1a (Dyrk1a), one of these triplicated genes, is an attractive target to normalize brain development due to its influence in cellular brain deficits seen in DS. We hypothesized that postnatal development of DYRK1A expression is dysregulated in trisomic animals, and found significant overexpression of DYRK1A in the hippocampus, cerebral cortex, and cerebellum at postnatal day (P) 15 in male—but not female—Ts65Dn mice. We then hypothesized the existence of sex-dependent effects of trisomy on neurobehavioral attributes during P16–17, and that administration of a DYRK1A inhibitor (CX-4945, ~75 mg/kg) beginning on P14 would normalize aberrant behavior in trisomic animals. Both male and female trisomic mice given control injections of phosphate buffered saline (PBS) displayed sustained levels of locomotor activity over a 10-minute test in contrast to the PBS-treated euploid animals that showed significant within-session habituation. Trisomic animals were more persistent in choosing to remain in home shavings in a preference test. Treatment with CX-4945 failed to confirm therapeutic effects. CX-4945 prevented growth, and both CX-4945 and its 10% dimethyl sulfoxide vehicle affected locomotor activity in trisomic and euploid groups, indicating a non-specific disruption of behavior. Despite the negative outcomes for CX-4945, the novel demonstration of sexually dimorphic DYRK1A expression in trisomic animals at P15 supports the broader hypothesis that overexpression of trisomic genes in DS can vary with age, sex, and brain region. Identifying the developmental timing of periods of dysregulated DYRK1A may be important for understanding individual differences in neurodevelopmental trajectories in DS and for developing effective therapeutic interventions targeting DYRK1A.
4 citations
TL;DR: The authors found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice.
Abstract: With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
4 citations
TL;DR: Antarakis SE Skotko BG Rafii MS et al. as discussed by the authors evaluated the safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome.
Abstract: Down syndrome is caused by an extra copy (or, rarely, an extra segment) of chromosome 21. The phenotype of Down syndrome is variable, but common to all individuals with the syndrome is some degree of intellectual disability. 1 Antonarakis SE Skotko BG Rafii MS et al. Down syndrome. Nat Rev Dis Primers. 2020; 6: 9 Crossref PubMed Scopus (92) Google Scholar Alzheimer's disease pathology is seen both at autopsy and by amyloid PET in all adults with Down syndrome by the age of 40 years, putting this population at especially high risk of developing early-onset Alzheimer's disease. However, there are no pharmacological treatments for either intellectual disability or Alzheimer's disease in people with Down syndrome. Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trialMemantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work. Full-Text PDF
4 citations
TL;DR: It is shown that trisomic mice accumulate soluble Aβ40‐42 in the basal forebrain, frontal cortex, hippocampus, and cerebellum in an age‐specific manner, with elevation in the frontal cortex and hippocampus as early as 4 months of age.
Abstract: Down syndrome (DS) is a leading cause of intellectual disability that also results in hallmark Alzheimer's disease (AD) pathologies such as amyloid beta (Aβ) plaques and hyperphosphorylated tau. The Ts65Dn mouse model is commonly used to study DS, as trisomic Ts65Dn mice carry 2/3 of the triplicated gene homologues as occur in human DS. The Ts65Dn strain also allows investigation of mechanisms common to DS and AD pathology, with many of these triplicated genes implicated in AD; for example, trisomic Ts65Dn mice overproduce amyloid precursor protein (APP), which is then processed into soluble Aβ40‐42 fragments. Notably, Ts65Dn mice show alterations to the basal forebrain, which parallels the loss of function in this region observed in DS and AD patients early on in disease progression. However, a complete picture of soluble Aβ40‐42 accumulation in a region‐, age‐, and sex‐specific manner has not yet been characterized in the Ts65Dn model. Here, we show that trisomic mice accumulate soluble Aβ40‐42 in the basal forebrain, frontal cortex, hippocampus, and cerebellum in an age‐specific manner, with elevation in the frontal cortex and hippocampus as early as 4 months of age. Furthermore, we detected sex differences in accumulation of Aβ40‐42 within the basal forebrain, with females having significantly higher Aβ40‐42 at 7–8 months of age. Lastly, we show that APP expression in the basal forebrain and hippocampus inversely correlates with Aβ40‐42 levels. This spatial and temporal characterization of soluble Aβ40‐42 in the Ts65Dn model allows for further exploration of the role soluble Aβ plays in the progression of other AD‐like pathologies in these key brain regions.
4 citations
TL;DR: In this article , the authors compare the cellular phenotypes of chromosome 21 trisomy with other trisomic cells and argue that both effects of the extra chromosome 21 and the global consequences of chromosome gain must be considered to understand complex pathologies of Down syndrome.
3 citations
TL;DR: Results demonstrated that trisomy rescue may be a phenomenon with random loss of the extra chromosome and subsequent selection for disomic iPSCs, which is analogous to the karyotype correction in early preimplantation embryos.
Abstract: Trisomy 21, 18, and 13 are the major autosomal aneuploidy disorders in humans. They are mostly derived from chromosome non-disjunction in maternal meiosis, and the extra trisomic chromosome can cause several congenital malformations. Various genes on the trisomic chromosomes are intricately involved in the development of disease, and fundamental treatments have not yet been established. However, chromosome therapy has been developed to correct the extra chromosome in cultured patient cells, and it was recently reported that during reprogramming into iPSCs, fibroblasts from a Down syndrome patient lost the extra chromosome 21 due to a phenomenon called trisomy-biased chromosome loss. To gain preliminary insights into the underlying mechanism of trisomy rescue during the early stages of reprogramming, we reprogrammed skin fibroblasts from patients with trisomy syndromes 21, 18, 13, and 9 to iPSC, and evaluated the genomes of the individual iPSC colonies by molecular cytogenetic techniques. We report the spontaneous correction from trisomy to disomy upon cell reprogramming in at least one cell line examined from each of the trisomy syndromes, and three possible combinations of chromosomes were selected in the isogenic trisomy-rescued iPSC clones. Single nucleotide polymorphism analysis showed that the trisomy-rescued clones exhibited either heterodisomy or segmental uniparental isodisomy, ruling out the possibility that two trisomic chromosomes were lost simultaneously and the remaining one was duplicated, suggesting instead that one trisomic chromosome was lost to generate disomic cells. These results demonstrated that trisomy rescue may be a phenomenon with random loss of the extra chromosome and subsequent selection for disomic iPSCs, which is analogous to the karyotype correction in early preimplantation embryos. Our finding is relevant for elucidating the mechanisms of autonomous karyotype correction and future application in basic and clinical research on aneuploidy disorders.
TL;DR: Rodent preclinical models of AD-DS are reviewed and how these can be used for both in vivo and ex vivo studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.
Abstract: There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.
TL;DR: Ts66Yah as mentioned in this paper is the first mouse model to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to HSA21, which is also related to our work.
Abstract: Down syndrome is caused by trisomy of human chromosome 21 (Hsa21). The understanding of phenotype-genotype relationships, the identification of driver genes and various proof-of-concepts for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to the human DS features. It carries an additional minichromosome with the Mir155 to Zbtb21 region of mouse chromosome 16 (Mmu16), homologous to Hsa21, encompassing around 90 genes, fused to the centromeric part of mouse chromosome 17 (Mmu17) fromPisd-ps2/Scaf8 to Pde10a, containing 46 genes, not related to Hsa21. Here, we report the investigation of a new model, Ts66Yah, generated by CrispR/Cas9 without the genomic region unrelated to Hsa21 on the minichromosome. As expected, Ts66Yah replicated DS cognitive features. However, certain phenotypes related to increased activity, spatial learning and molecular signatures, were changed suggesting genetic interactions between the Mir155-Zbtb21 and the Scaf8-Pde10a interval. Thus, Ts66Yah mice have a stronger construct and face validity for mimicking consequences of DS genetic overdosage. Furthermore, this report is the first to demonstrate genetic interactions between triplicated regions homologous to Hsa21 and others unrelated to Hsa21.
TL;DR: In this article , a review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models.
Abstract: Down syndrome (DS), also known as trisomy 21, is a genetic disorder caused by triplication of Chromosome 21. Gene triplication may compromise different body functions but invariably impairs intellectual abilities starting from infancy. Moreover, after the fourth decade of life people with DS are likely to develop Alzheimer’s disease. Neurogenesis impairment during fetal life stages and dendritic pathology emerging in early infancy are thought to be key determinants of alterations in brain functioning in DS. Although the progressive improvement in medical care has led to a notable increase in life expectancy for people with DS, there are currently no treatments for intellectual disability. Increasing evidence in mouse models of DS reveals that pharmacological interventions in the embryonic and neonatal periods may greatly benefit brain development and cognitive performance. The most striking results have been obtained with pharmacotherapies during embryonic life stages, indicating that it is possible to pharmacologically rescue the severe neurodevelopmental defects linked to the trisomic condition. These findings provide hope that similar benefits may be possible for people with DS. This review summarizes current knowledge regarding (i) the scope and timeline of neurogenesis (and dendritic) alterations in DS, in order to delineate suitable windows for treatment; (ii) the role of triplicated genes that are most likely to be the key determinants of these alterations, in order to highlight possible therapeutic targets; and (iii) prenatal and neonatal treatments that have proved to be effective in mouse models, in order to rationalize the choice of treatment for human application. Based on this body of evidence we will discuss prospects and challenges for fetal therapy in individuals with DS as a potential means of drastically counteracting the deleterious effects of gene triplication.
TL;DR: In this paper , a case series of three acute myeloid leukemia (AML) patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe was described.
Abstract: 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized.Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks.Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes.
TL;DR: Interferon receptor gene dosage determines major hallmarks of Down syndrome, indicating that trisomy 21 elicits an interferonopathy amenable to therapeutic intervention.
Abstract: Trisomy 21 causes Down syndrome, a condition characterized by cognitive impairments, immune dysregulation, and atypical morphogenesis. Using whole blood transcriptome analysis, we demonstrate that specific overexpression of four interferon receptors encoded on chromosome 21 associates with chronic interferon hyperactivity and systemic inflammation in Down syndrome. To define the contribution of interferon receptor overexpression to Down syndrome phenotypes, we used genome editing to correct interferon receptor gene dosage in mice carrying triplication of a large genomic region orthologous to human chromosome 21. Normalization of interferon receptor copy number attenuated lethal antiviral responses, prevented heart malformations, decreased developmental delays, improved cognition and normalized craniofacial anomalies. Therefore, interferon receptor gene dosage determines major hallmarks of Down syndrome, indicating that trisomy 21 elicits an interferonopathy amenable to therapeutic intervention. One-Sentence Summary Correction of interferon receptor gene dosage rescues multiple key phenotypes in a mouse model of trisomy 21.
TL;DR: It is suggested that trisomy of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may be one major reason why preclinical trials that used this model have unsuccessfully translated to human therapies.
01 Jan 2022
TL;DR: The advantages of performing genetic studies in people with DS, the role of reported genes that are known to be associated with AD risk in adults with DS or in the general population are discussed, and how future longitudinal multiomic and imaging study can enhance the understanding of the biology of AD are discussed.
Abstract: Down syndrome (DS) is one of the most common genetic diseases, and adults with DS show neuropathological signs of Alzheimer's disease (AD) starting at age 40 years of age, and nearly one-half will develop dementia by age 60, owing to triplication and overexpression of the APP gene on chromosome 21. Beyond the amyloid precursor protein (APP) gene located on chromosome 21, it is necessary to examine other genes on chromosome 21 and genes outside chromosome 21 to explain the wide range of age at onset and phenotypic expression in adults with DS. To date, only a limited number of candidate gene studies and one genome-wide association study have been reported in adults with DS. Here, we discuss the advantages of performing genetic studies in people with DS, and then discuss the role of reported genes that are known to be associated with AD risk in adults with DS or in the general population. Lastly, we discuss how future longitudinal multiomic and imaging study can enhance our understanding of the biology of AD.
01 Apr 2022
TL;DR: In this article , the limitations of mouse models of DS and how these can be addressed using recent advancements in modelling DS using human iPSCs and iPSC-mouse chimeras, and potential applications of human-induced pluripotent stem cells (iPSCs) in preclinical studies for DS-AD.
Abstract: Down syndrome (DS) is the most common chromosomal abnormality and leads to intellectual disability, increased risk of cardiac defects, and an altered immune response. Individuals with DS have an extra full or partial copy of chromosome 21 (trisomy 21) and are more likely to develop early-onset Alzheimer's disease (AD) than the general population. Changes in expression of human chromosome 21 (Hsa21)-encoded genes, such as amyloid precursor protein (APP), play an important role in the pathogenesis of AD in DS (DS-AD). However, the mechanisms of DS-AD remain poorly understood. To date, several mouse models with an extra copy of genes syntenic to Hsa21 have been developed to characterise DS-AD-related phenotypes. Nonetheless, due to genetic and physiological differences between mouse and human, mouse models cannot faithfully recapitulate all features of DS-AD. Cells differentiated from human-induced pluripotent stem cells (iPSCs), isolated from individuals with genetic diseases, can be used to model disease-related cellular and molecular pathologies, including DS. In this review, we will discuss the limitations of mouse models of DS and how these can be addressed using recent advancements in modelling DS using human iPSCs and iPSC-mouse chimeras, and potential applications of iPSCs in preclinical studies for DS-AD.
TL;DR: In this article , the authors compare the molecular consequences of trisomy syndromes in vivo against engineered cell lines carrying various chromosome gains in vitro, and point out several phenotypes that are shared by variable trisomies and, therefore, might be caused by the presence of an extra chromosome per se, independent of its identity.
Abstract: Chromosome gains are detrimental for the development of the human embryo. As such, autosomal trisomies almost always result in spontaneous abortion, and the rare embryos surviving until live birth suffer from a plethora of pathological defects. There is no treatment currently available to ameliorate the consequences of trisomies, such as Down syndrome (trisomy of chromosome 21). Identifying the source of the phenotypes observed in cells with extra chromosomes is crucial for understanding the underlying molecular causes of trisomy syndromes. Although increased expression of the genes localized on the extra chromosome triggers several pathological phenotypes, an alternative model suggests that global, aneuploidy-associated changes in cellular physiology also contribute to the pathology. Here, we compare the molecular consequences of trisomy syndromes in vivo against engineered cell lines carrying various chromosome gains in vitro. We point out several phenotypes that are shared by variable trisomies and, therefore, might be caused by the presence of an extra chromosome per se, independent of its identity. This alternative view may provide useful insights for understanding Down syndrome pathology and open additional opportunities for diagnostics and treatments.
TL;DR: PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology was demonstrated and targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory.
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease which is becoming increasingly prevalent due to ageing populations resulting in huge social, economic, and health costs to the community. Despite the pathological processing of genes such as Amyloid Precursor Protein (APP) into Amyloid-β and Microtubule Associated Protein Tau (MAPT) gene, into hyperphosphorylated Tau tangles being known for decades, there remains no treatments to halt disease progression. One population with increased risk of AD are people with Down syndrome (DS), who have a 90% lifetime incidence of AD, due to trisomy of human chromosome 21 (HSA21) resulting in three copies of APP and other AD-associated genes, such as DYRK1A (Dual specificity tyrosine-phosphorylation-regulated kinase 1A) overexpression. This suggests that blocking DYRK1A might have therapeutic potential. However, it is still not clear to what extent DYRK1A overexpression by itself leads to AD-like phenotypes and how these compare to Tau and Amyloid-β mediated pathology. Likewise, it is still not known how effective a DYRK1A antagonist may be at preventing or improving any Tau, Amyloid-β and DYRK1a mediated phenotype. To address these outstanding questions, we characterised Drosophila models with targeted overexpression of human Tau, human Amyloid-β or the fly orthologue of DYRK1A, called minibrain (mnb). We found targeted overexpression of these AD-associated genes caused degeneration of photoreceptor neurons, shortened lifespan, as well as causing loss of locomotor performance, sleep, and memory. Treatment with the experimental DYRK1A inhibitor PST-001 decreased pathological phosphorylation of human Tau [at serine (S) 262]. PST-001 reduced degeneration caused by human Tau, Amyloid-β or mnb lengthening lifespan as well as improving locomotion, sleep and memory loss caused by expression of these AD and DS genes. This demonstrated PST-001 effectiveness as a potential new therapeutic targeting AD and DS pathology.
TL;DR: It is found that in human fetal fibroblasts with chromosome 21 trisomy there is increased expression of both RUNX1 and several ECM genes, whether located on chromosome 21 or not, and this increased expression increased the migratory capacity of trisomic fibro Blasts, which are characterized by a reduced migratorycapacity compared to euploid controls.
Abstract: Down syndrome is a neurodevelopmental disorder frequently characterized by other developmental defects, such as congenital heart disease. Analysis of gene expression profiles of hearts from trisomic fetuses have shown upregulation of extracellular matrix (ECM) genes. The aim of this work was to identify genes on chromosome 21 potentially responsible for the upregulation of ECM genes and to pinpoint any functional consequences of this upregulation. By gene set enrichment analysis of public data sets, we identified the transcription factor RUNX1, which maps to chromosome 21, as a possible candidate for regulation of ECM genes. We assessed that approximately 80% of ECM genes overexpressed in trisomic hearts have consensus sequences for RUNX1 in their promoters. We found that in human fetal fibroblasts with chromosome 21 trisomy there is increased expression of both RUNX1 and several ECM genes, whether located on chromosome 21 or not. SiRNA silencing of RUNX1 reduced the expression of 11 of the 14 ECM genes analyzed. In addition, collagen IV, an ECM protein secreted in high concentrations in the culture media of trisomic fibroblasts, was modulated by RUNX1 silencing. Attenuated expression of RUNX1 increased the migratory capacity of trisomic fibroblasts, which are characterized by a reduced migratory capacity compared to euploid controls.
TL;DR: In this article , the authors used a combination of next-generation mouse models of DS (Tc1, Dp3Tyb and Dp(10)2Yey) and a knockin mouse model of Aβ accumulation (NL-F) to determine how chromosome 21 genes, other than APP, modulate APP/Aβ in the brain when in three copies.
Abstract: Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer9s disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation (AppNL-F) to determine how chromosome 21 genes, other than APP, modulate APP/Aβ in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aβ accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aβ accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2. Thus, an additional copy of chromosome 21 genes, other than APP, can modulate APP/Aβ in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP. SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer9s disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein (APP) gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aβ accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.
TL;DR: In this article , the authors performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 5 different intermediates of the one-carbon cycle in plasma samples obtained from a total of 164 subjects with Down syndrome compared to 54 euploid subjects.
Abstract: Introduction Down syndrome (DS) is the most common chromosomal disorder and it is caused by trisomy of chromosome 21 (Hsa21). Subjects with DS show a large heterogeneity of phenotypes and the most constant clinical features present are typical facies and intellectual disability (ID). Several studies demonstrated that trisomy 21 causes an alteration in the metabolic profile, involving among all the one-carbon cycle. Methods We performed enzyme-linked immunosorbent assays (ELISAs) to identify the concentration of 5 different intermediates of the one-carbon cycle in plasma samples obtained from a total of 164 subjects with DS compared to 54 euploid subjects. We investigated: tetrahydrofolate (THF; DS n = 108, control n = 41), 5-methyltetrahydrofolate (5-methyl-THF; DS n = 140, control n = 34), 5-formyltetrahydrofolate (5-formyl-THF; DS n = 80, control n = 21), S-adenosyl-homocysteine (SAH; DS n = 94, control n = 20) and S-adenosyl-methionine (SAM; DS n = 24, control n = 15). Results Results highlight specific alterations of THF with a median concentration ratio DS/control of 2:3, a decrease of a necessary molecule perfectly consistent with a chromosomal dosage effect. Moreover, SAM and SAH show a ratio DS/control of 1.82:1 and 3.6:1, respectively. Discussion The relevance of these results for the biology of intelligence and its impairment in trisomy 21 is discussed, leading to the final proposal of 5-methyl-THF as the best candidate for a clinical trial aimed at restoring the dysregulation of one-carbon cycle in trisomy 21, possibly improving cognitive skills of subjects with DS.
TL;DR: In this paper , a case series of three acute myeloid leukemia (AML) patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe was described.
Abstract: 21q22 amplification is a rare cytogenetic aberration in acute myeloid leukemia (AML). So far, the cytogenomic and molecular features and clinical correlation of 21q22 amplification in AML have not been well-characterized.Here, we describe a case series of three AML patients with amplified 21q22 identified by fluorescence in situ hybridization using a RUNX1 probe. Two of these patients presented with therapy-related AML (t-AML) secondary to chemotherapy, while the third had de novo AML. There was one case each of FAB M0, M1 and M4. Morphologic evidence of dysplasia was identified in both t-AML cases. Phenotypic abnormalities of the myeloblasts were frequently observed. Extra copies of 21q22 were present on chromosome 21 and at least one other chromosome in two cases. Two showed a highly complex karyotype. Microarray analysis of 21q22 amplification in one case demonstrated alternating levels of high copy number gain split within the RUNX1 locus at 21q22. The same patient also had mutated TP53. Two patients died at 1.5 and 11 months post-treatment, while the third elected palliative care and died within 2 weeks.Our results provide further evidence that 21q22 amplification in AML is associated with complex karyotypes, TP53 aberrations, and poor outcomes. Furthermore, we demonstrate that 21q22 amplification is not always intrachromosomally localized to chromosome 21 and could be a result of structural aberrations involving 21q22 and other chromosomes.
01 Jan 2022
TL;DR: In this paper , the authors explore the neuroinflammatory consequences of AD pathology in the brain, and how this may be unique in DS due to the triplication of immune-associated genes also located on chromosome 21.
Abstract: Down syndrome (DS), the most common genetic cause of intellectual disability, is characterized by the triplication of chromosome 21. The triplication of the amyloid precursor protein gene, amyloid precursor protein (APP), is thought to be the underlying reason why Alzheimer's disease (AD) pathology develops in the DS brain with age. In this chapter, we explore the neuroinflammatory consequences of AD pathology in the brain, and how this may be unique in DS due to the triplication of immune-associated genes also located on chromosome 21.
TL;DR: A large-scale yeast two-hybrid screen focusing on chromosome 21 proteins and their direct interactors revealed enrichment in proteins linked to synapse plasticity, autism, and Alzheimer’s disease.
Abstract: A large-scale (82) yeast two-hybrid screen focusing on chromosome 21 proteins and their direct interactors revealed enrichment in proteins linked to synapse plasticity, autism, and Alzheimer’s disease. Down syndrome (DS) is caused by human chromosome 21 (HSA21) trisomy. It is characterized by a poorly understood intellectual disability (ID). We studied two mouse models of DS, one with an extra copy of the Dyrk1A gene (189N3) and the other with an extra copy of the mouse Chr16 syntenic region (Dp(16)1Yey). RNA-seq analysis of the transcripts deregulated in the embryonic hippocampus revealed an enrichment in genes associated with chromatin for the 189N3 model, and synapses for the Dp(16)1Yey model. A large-scale yeast two-hybrid screen (82 different screens, including 72 HSA21 baits and 10 rebounds) of a human brain library containing at least 107 independent fragments identified 1,949 novel protein–protein interactions. The direct interactors of HSA21 baits and rebounds were significantly enriched in ID-related genes (P-value < 2.29 × 10−8). Proximity ligation assays showed that some of the proteins encoded by HSA21 were located at the dendritic spine postsynaptic density, in a protein network at the dendritic spine postsynapse. We located HSA21 DYRK1A and DSCAM, mutations of which increase the risk of autism spectrum disorder (ASD) 20-fold, in this postsynaptic network. We found that an intracellular domain of DSCAM bound either DLGs, which are multimeric scaffolds comprising receptors, ion channels and associated signaling proteins, or DYRK1A. The DYRK1A-DSCAM interaction domain is conserved in Drosophila and humans. The postsynaptic network was found to be enriched in proteins associated with ARC-related synaptic plasticity, ASD, and late-onset Alzheimer’s disease. These results highlight links between DS and brain diseases with a complex genetic basis.
01 Jan 2022
TL;DR: In this paper, the authors explore the neuroinflammatory consequences of AD pathology in the brain, and how this may be unique in DS due to the triplication of immune-associated genes also located on chromosome 21.
Abstract: Down syndrome (DS), the most common genetic cause of intellectual disability, is characterized by the triplication of chromosome 21. The triplication of the amyloid precursor protein gene, amyloid precursor protein (APP), is thought to be the underlying reason why Alzheimer's disease (AD) pathology develops in the DS brain with age. In this chapter, we explore the neuroinflammatory consequences of AD pathology in the brain, and how this may be unique in DS due to the triplication of immune-associated genes also located on chromosome 21.
TL;DR: Craniofacial dysmorphology in mouse models of Down syndrome is caused by increased dosage of at least four genes including Dyrk1a, resulting in reduced proliferation of neural crest-derived cranial bone progenitors.
Abstract: Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated genetic mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by increased dosage of Dyrk1a and at least three other genes. Summary statement Craniofacial dysmorphology in mouse models of Down syndrome is caused by increased dosage of at least four genes including Dyrk1a, resulting in reduced proliferation of neural crest-derived cranial bone progenitors.
TL;DR: In this article , the authors evaluated the application of the micronucleus assay and fluorescence in situ hybridization (FISH) for estimation of chromosome instability and occurrence of trisomy 21 in young parents having pregnancy or a child with the regular form of Down syndrome.
Abstract: Although the risk of pregnancy with Down syndrome (DS) increases with age, conceptions with trisomy 21 can occur in mothers aged 35 or less. The micronucleus test on peripheral blood lymphocytes is a well-recognized method for studying chromosomal instability. The aim of this study was to evaluate the application of the micronucleus assay and fluorescence in situ hybridization (FISH) for estimation of chromosome instability and occurrence of trisomy 21 in young parents having pregnancy or a child with the regular form of Down syndrome. The study included 54 parents (27 couples) who had previous pregnancy with trisomy 21 at age 35 or less. The control group consisted of 30 couples with two healthy children and no previous spontaneous abortions. Parents with trisomy 21 pregnancy had significantly higher frequencies of micronuclei in binucleated cells. There was no statistically significant difference between the study and control groups in the frequencies of micronuclei in mononuclear cells, nuclear buds, or nucleoplasmic bridges. FISH analysis showed higher percentages of micronuclei containing whole chromosomes as well as statistically significant higher numbers of micronuclei containing chromosome 21 in the peripheral blood of DS parents. There was no statistically significant difference between the two groups in the responses of peripheral blood lymphocytes to treatment with the mutagen mitomycin C. Our results suggest that young parents with a history of the regular form of Down syndrome have a higher susceptibility to chromosome nondisjunction in peripheral blood lymphocytes. The micronucleus assay showed high specificity, but moderate sensitivity, for risk assessment of trisomy 21 pregnancy.