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Mouse models of Down syndrome: gene content and consequences.

ABSTRACT: Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are as follows: (i) it is trisomic for 125 human protein-coding orthologs, but only 90 of these are Hsa21 orthologs and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret the results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review the functional information on Hsa21 protein-coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.

SUBMITTER: Gupta M

PROVIDER: S-EPMC5471624 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Mouse models of Down syndrome: gene content and consequences.

Gupta Meenal M Dhanasekaran A Ranjitha AR Gardiner Katheleen J KJ

Mammalian genome : official journal of the International Mammalian Genome Society 20160818 11-12

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17, and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are as follows: (i) it is triso ...[more]

PMID: 27538963

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Project description:The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct age-dependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

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Mouse models of Down syndrome: gene content and consequences.

Publications

Mouse models of Down syndrome: gene content and consequences.

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