Neurodevelopment in Down syndrome: Concordance in humans and models

Klein, Jenny A.; Haydar, Tarik F.

doi:10.3389/fncel.2022.941855

Cited by 14 publications

(13 citation statements)

References 104 publications

(144 reference statements)

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“…The genetic validity of available murine models for the study of DS phenotype has been a topic of strong debate in the last decade [3,[33][34][35][36]. To improve the representation of DS human genotype and phenotype in mice, Herault and colleagues developed new line named Ts66Yah, derived from the Ts65Dn lineage but no longer carrying the duplicated centromeric part of Mmu17, [20].…”

Section: Discussionmentioning

confidence: 99%

Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging

Lanzillotta,

Baniowska,

Prestia

et al. 2024

Preprint

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Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy ofHomo sapienschromosome 21 (HSA21). The increased dosage of genes on HSA21 is the cause for the initial neurodevelopmental disorder and for further development of cognitive decline, however the molecular mechanisms promoting brain pathology along ageing are still missing. One of the major challenges in the study of DS is the lack of reliable murine model able to accurately replicate genotypic and phenotypic aspects observed in humans along ageing. Preclinical studies in DS were pioneered using the Ts65Dn murine model, which despite its genetic limitations, has been extremely helpful in characterising the progression of brain degeneration. The novel Ts66Yah model represents an evolution of the Ts65Dn, with phenotypes only induced by trisomic HSA21 homologous genes, closer to human DS condition. In this study, we confirmed the behavioural features of Ts66Yah mice with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The molecular characterisation of Ts66Yah demonstrated the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-related alterations of those pathways occur early promoting the alteration of brain development and the onset of a condition of premature aging. Overall, data collected in Ts66Yah provide novel and consolidated insights, devoid of genome bias, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.

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Section: Discussionmentioning

confidence: 99%

Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging

Lanzillotta,

Baniowska,

Prestia

et al. 2024

Preprint

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“…While some individuals with DS (2%–4%) are mosaic for trisomy 21 (T21), i.e., two or more genetically distinct cells develop from a single zygote resulting in a proportion of cells harboring T21 and a subset that are euploid ( Papavassiliou et al, 2009 ), the vast majority of individuals with DS exhibit T21 in all cells. The variable penetrance of DS-related cognitive phenotypes has likely contributed to some of the discrepancies observed in human postmortem studies and concordance with model systems, i.e., mice and human cell culture ( Manley and Anderson, 2019 ; Klein and Haydar, 2022 ).…”

Section: Neurological Features Of Down Syndromementioning

confidence: 99%

“…In spite of this, some features are consistent, including the fact that individuals with DS exhibit atypical neurodevelopment with effects that persist into adulthood ( Klein and Haydar, 2022 ). The most prominent neurological features of DS include reduced brain size, altered cell type composition, abnormal neuronal communication and network activity, pathological hallmarks of Alzheimer’s disease, and neuroinflammation, which are all believed to contribute to altered brain function that results in intellectual disability and an increased risk of early-onset dementia ( Figure 1 ).…”

Section: Neurological Features Of Down Syndromementioning

confidence: 99%

“…Rodent models of human neurological disorders are only as useful as their ability to recapitulate disease phenotypes. While several DS mouse strains model some aspects of the disorder and have provided significant insight into the cellular and molecular mechanisms underlying those specific phenotypes, there does not exist a single model that exhibits all of the clinical features observed in humans with DS [reviewed in ( Klein and Haydar, 2022 )]. There are also key differences between rodent and human brain cell types, such as astrocytes ( Oberheim et al, 2009 ) and microglia ( Gosselin et al, 2017 ), in terms of transcriptional profiles and functional characteristics, suggesting that the study of human brain cell types is more appropriate to gain insights into human neurological disease.…”

Section: Rodent Models Of Down Syndromementioning

confidence: 99%

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From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome

Watson

Meharena

2023

Front. Genet.

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Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent aneuploidy observed in the human population and represents the most common genetic form of intellectual disability and early-onset Alzheimer’s disease (AD). Individuals with DS exhibit a wide spectrum of clinical presentation, with a number of organs implicated including the neurological, immune, musculoskeletal, cardiac, and gastrointestinal systems. Decades of DS research have illuminated our understanding of the disorder, however many of the features that limit quality of life and independence of individuals with DS, including intellectual disability and early-onset dementia, remain poorly understood. This lack of knowledge of the cellular and molecular mechanisms leading to neurological features of DS has caused significant roadblocks in developing effective therapeutic strategies to improve quality of life for individuals with DS. Recent technological advances in human stem cell culture methods, genome editing approaches, and single-cell transcriptomics have provided paradigm-shifting insights into complex neurological diseases such as DS. Here, we review novel neurological disease modeling approaches, how they have been used to study DS, and what questions might be addressed in the future using these innovative tools.

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“…It is noteworthy that in the mouse and human cerebellum, there is also a decrease in the number of granule and Purkinje cells [ 10 , 200 , 209 , 210 ]. For the updated and comprehensive review describing DS-related developmental brain changes across different mouse models and cellular systems, please refer to Klein and Haydar [ 211 ].…”

Section: Introductionmentioning

confidence: 99%

Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain

Farley

Grishok

Zeldich

2022

Epigenetics & Chromatin

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Intellectual disability is a well-known hallmark of Down Syndrome (DS) that results from the triplication of the critical region of human chromosome 21 (HSA21). Major studies were conducted in recent years to gain an understanding about the contribution of individual triplicated genes to DS-related brain pathology. Global transcriptomic alterations and widespread changes in the establishment of neural lineages, as well as their differentiation and functional maturity, suggest genome-wide chromatin organization alterations in trisomy. High Mobility Group Nucleosome Binding Domain 1 (HMGN1), expressed from HSA21, is a chromatin remodeling protein that facilitates chromatin decompaction and is associated with acetylated lysine 27 on histone H3 (H3K27ac), a mark correlated with active transcription. Recent studies causatively linked overexpression of HMGN1 in trisomy and the development of DS-associated B cell acute lymphoblastic leukemia (B-ALL). HMGN1 has been shown to antagonize the activity of the Polycomb Repressive Complex 2 (PRC2) and prevent the deposition of histone H3 lysine 27 trimethylation mark (H3K27me3), which is associated with transcriptional repression and gene silencing. However, the possible ramifications of the increased levels of HMGN1 through the derepression of PRC2 target genes on brain cell pathology have not gained attention. In this review, we discuss the functional significance of HMGN1 in brain development and summarize accumulating reports about the essential role of PRC2 in the development of the neural system. Mechanistic understanding of how overexpression of HMGN1 may contribute to aberrant brain cell phenotypes in DS, such as altered proliferation of neural progenitors, abnormal cortical architecture, diminished myelination, neurodegeneration, and Alzheimer’s disease-related pathology in trisomy 21, will facilitate the development of DS therapeutic approaches targeting chromatin.

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Neurodevelopment in Down syndrome: Concordance in humans and models

Cited by 14 publications

References 104 publications

Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging

Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging

From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome

Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain

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