Trisomy 21, Down syndrome (DS), affects approximately 400,000 people in the U.S., causing cognitive disability, which includes the neuropathology of Alzheimer's disease and late-life dementia. Based on the prevailing gene dosage effect hypothesis, a cognitively relevant phenotype in DS is caused by the triplication of one or more human chromosome (HSA) 21 genes. Our preliminary observations from the mouse-based studies suggest that these causative genes are indeed present and the search for them is both possible and productive. The long-term objective of this project is to identify these causative genes by using mouse-based genetic analysis, which is built upon the recent successes of our team: (1) We have developed two optimal reference mouse models for DS using efficient Cre/loxP-mediated chromosome engineering: Dp(16)1Yu/+, which is trisomic for the entire 22.9-Mb HSA21 syntenic region on mouse chromosome (MMU) 16, and Dp(10)1Yu/+;Dp(16)1Yu/+;Dp(17)1Yu/+, which is trisomic for all three HSA21 syntenic regions on MMU10, MMU16 and MMU17. (2) We have narrowed down the genomic region associated with the cognitive disability of DS to the smallest segment in the mouse genome: the Cbr1-Fam3b chromosomal segment containing 30 HSA21 gene orthologs. The triplication of this segment in mice causes abnormalities in cognitive behaviors, synaptic structures and hippocampal long-term potentiation, a major cellular mechanism that underlies learning and memory. To achieve our objective, we propose, in Specific Aim 1 of this application, to characterize the most important cognitively relevant phenotypes of the optimal reference mouse models for DS. To establish the basic phenotypic parameters to facilitate the genetic dissection, we will characterize the synaptic structures and plasticity in the hippocampus as well as cognitive behaviors of Dp(16)1Yu/+ and Dp(10)1Yu/+;Dp(16)1Yu/+;Dp(17)1Yu/+ mice. We will also measure the size and number of neurons in the hippocampal circuits of Dp(16)1/+ mice at the different ages to ascertain the neurodegenerative phenotype.
In Specific Aim 2, we will analyze the Cbr1-Famb3b segment to identify a minimal genomic region for the DS- associated synaptic and cognitive phenotypes. We will generate new mouse mutants carrying nested duplications and deletions within the Cbr1-Fam3b segment by chromosome engineering and, by using these mutants, we will employ a subtractive/additive strategy in which synaptic and cognitive phenotypes are linked to progressively smaller genomic segments until a minimal critical region is defined. This effort will lay the groundwork to identify a causative gene(s) located within the minimal critical region(s) for these phenotypes, which will set the stage for the unraveling of the molecular mechanism of DS-associated cognitive disability as well as provide the conclusive support for the aforementioned hypothesis. Therefore, we expect, through these studies, to considerably accelerate progress in understanding and treating cognitive disability in DS.

Public Health Relevance

Cognitive dysfunction affects essentially all children and adults with trisomy 21, Down syndrome (DS);with no effective treatments available, fully 400,000 people in the U.S. experience developmental delays in mental function as children and progressive decline of cognitive skills associated with the neuropathology of Alzheimer's disease during aging. Innovative approaches to unraveling the underlying mechanisms and to developing effective therapies are urgently needed. We propose to use chromosome engineering to create new mouse mutants to define linkages between cognitively relevant phenotypes of DS and minimal critical genomic regions, with the ultimate goal of identifying the causative genes, an accomplishment that would greatly accelerate progress toward understanding and treating cognitive dysfunction in DS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066072-05
Application #
8725237
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Riddle, Robert D
Project Start
2010-09-30
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Xu-Qiao; Sawa, Mariko; Mobley, William C (2018) Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome. Free Radic Biol Med 114:52-61
Liu, Chunhong; Yu, Tao; Xing, Zhuo et al. (2018) Triplications of human chromosome 21 orthologous regions in mice result in expansion of megakaryocyte-erythroid progenitors and reduction of granulocyte-macrophage progenitors. Oncotarget 9:4773-4786
Bradshaw, Ralph A; Mobley, William; Rush, Robert A (2017) Nerve Growth Factor and Related Substances: A Brief History and an Introduction to the International NGF Meeting Series. Int J Mol Sci 18:
Herault, Yann; Delabar, Jean M; Fisher, Elizabeth M C et al. (2017) Rodent models in Down syndrome research: impact and future opportunities. Dis Model Mech 10:1165-1186
Kleschevnikov, Alexander M; Yu, Jessica; Kim, Jeesun et al. (2017) Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis 103:1-10
Do, Catherine; Xing, Zhuo; Yu, Y Eugene et al. (2017) Trans-acting epigenetic effects of chromosomal aneuploidies: lessons from Down syndrome and mouse models. Epigenomics 9:189-207
Mojabi, Fatemeh S; Fahimi, Atoossa; Moghadam, Shahrzad et al. (2016) GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: Exploring the role of App. Hippocampus 26:1641-1654
Xing, Zhuo; Li, Yichen; Pao, Annie et al. (2016) Mouse-based genetic modeling and analysis of Down syndrome. Br Med Bull 120:111-122
Belichenko, Pavel V; Madani, Rime; Rey-Bellet, Lorianne et al. (2016) An Anti-?-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. PLoS One 11:e0152471
Ballard, Clive; Mobley, William; Hardy, John et al. (2016) Dementia in Down's syndrome. Lancet Neurol 15:622-36

Showing the most recent 10 out of 37 publications