The Use of Mouse Models for Understanding the Biology of Down Syndrome and Aging

Abstract

<jats:p>Down syndrome is a complex condition caused by trisomy of human chromosome 21. The biology of aging may be different in individuals with Down syndrome; this is not well understood in any organism. Because of its complexity, many aspects of Down syndrome must be studied either in humans or in animal models. Studies in humans are essential but are limited for ethical and practical reasons. Fortunately, genetically altered mice can serve as extremely useful models of Down syndrome, and progress in their production and analysis has been remarkable. Here, we describe various mouse models that have been used to study Down syndrome. We focus on segmental trisomies of mouse chromosome regions syntenic to human chromosome 21, mice in which individual genes have been introduced, or mice in which genes have been silenced by targeted mutagenesis. We selected a limited number of genes for which considerable evidence links them to aspects of Down syndrome, and about which much is known regarding their function. We focused on genes important for brain and cognitive function, and for the altered cancer spectrum seen in individuals with Down syndrome. We conclude with observations on the usefulness of mouse models and speculation on future directions.</jats:p>

Identification of a DNA methylation signature in blood cells from persons with Down Syndrome

“…As an alternative to the DSCR theory, the “organicist concept” centers the DS pathogenesis on the developmental process and suggests that the presence of a trisomic chromosome, beside the specific function of the genes that it contains, disrupts on the whole the genetic homeostasis and leads to developmental instability. Both murine [ 55 , 56 ] and human models [ 57 , 58 ] have recently argued against the existence of a unique DSCR, proposing that HSA21 contains different susceptibility regions that can contribute to the DS phenotype. Based on these and on other data, current researchers favour a synthesis of the two theories, in which the combination of the trisomy of multiple HSA21 genes, none of which is by itself critical for the disease, induces a wide-range cascade of events that through physical and functional interactions engages many non-HSA21 genes and results in a global remodeling of genomic function.…”

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

“…Among other HSA21 candidates, the triplication of some microRNAs (miRNAs), in particular miR-155 (Mashima, 2015), may further contribute to modulate target genes leading to changes of neurochemical metabolites, mitochondrial deficits, and other pathological conditions observed in DS individuals (Quinones-Lombrana and Blanco, 2015). Further, experimental evidence obtained in trisomic and monosomic mouse models allowed identification of regions outside the DSCR that are responsive to dosage that may contribute to defects in behavior and cognition and other DS pathological features (Vacano et al, 2012;Gupta et al, 2016).…”

Avances Citogenéticos y Neurobiológicos en el Síndrome de Down

“…Currently, most studies are based on animal models, mainly by the multiple advantages they present (Liu et al, 2011;Vacano, Duvak & Patterson, 2012). These models date back to 1973-74, when the first two genes located on HSA21were identified and for the first time mice with trisomy of chromosome 16 (MMU16), chromosome that is homologous to HSA21, were produced (Salehi, Faizi, Belichenko & Mobley, 2007).…”

“…Although the findings of these animal models are still scarce and its practical application is still limited, it may be considered that, in addition to providing basic information about the underlying etiology to DS, it is possible that their study also provide information, which on its basis early pharmacological interventions could be developed that prevent or compensate the appearance of some of the neuropsychological manifestations of DS (Gardiner, 2009;Rueda et al, 2012;Scorza andCavalheiro, 2011, Liu et al, 2011;Vacano et al, 2012) .…”