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Genetic Loss (genetic + loss)
Selected AbstractsGenetic loss of D-amino acid oxidase activity reverses schizophrenia-like phenotypes in miceGENES, BRAIN AND BEHAVIOR, Issue 1 2010V. Labrie Reduced function of the N -methyl- d -aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine binding site in its NR1 subunit that may be a useful target for the treatment of schizophrenia. In this study, we assessed the therapeutic potential of long-term increases in the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO) in mice. The effects of eliminating DAO function were investigated in mice that display schizophrenia-related behavioral deficits due to a mutation (Grin 1D481N) in the NR1 subunit that results in a reduction in NMDAR glycine affinity. Grin 1D481N mice show deficits in sociability, prolonged latent inhibition, enhanced startle reactivity and impaired spatial memory. The hypofunctional Dao 1G181R mutation elevated brain levels of D-serine, but alone it did not affect performance in the behavioral measures. Compared to animals with only the Grin 1D481N mutation, mice with both the Dao1G181R and Grin 1D481N mutations displayed an improvement in social approach and spatial memory retention, as well as a reversal of abnormally persistent latent inhibition and a partial normalization of startle responses. Thus, an increased level of D-serine resulting from decreased catalysis corrected the performance of mice with deficient NMDAR glycine site activation in behavioral tasks relevant to the negative and cognitive symptoms of schizophrenia. Diminished DAO activity and elevations in D-serine may serve as an effective therapeutic intervention for the treatment of psychiatric symptoms. [source] Genome-wide amplification and allelotyping of sporadic pituitary adenomas identify novel regions of genetic lossGENES, CHROMOSOMES AND CANCER, Issue 3 2003D. J. Simpson Through the use of a candidate gene approach, several previous studies have identified loss of heterozygosity (LOH) at putative tumor-suppressor gene (TSG) loci in sporadic pituitary tumors. This study reports a genome-wide allelotyping by use of 122 microsatellite markers in a large cohort of tumors, consisting of somatotrophinomas and non-functioning adenomas. Samples were first subject to prior whole genome amplification by primer extension pre-amplification (PEP) to circumvent limitations imposed by insufficient DNA for whole-genome analysis with this number of microsatellite markers. The overall mean frequency of loss in invasive tumors was significantly higher than that in their non-invasive counterparts (7 vs. 3% somatotrophinomas; 6 vs. 3% non-functioning adenomas, respectively). Analysis of the mean frequency of LOH, across all markers to individual chromosomal arms, identified 13 chromosomal arms in somatotrophinomas and 10 in non-functioning tumors, with LOH greater than the 99% upper confidence interval calculated for the rate of overall random allelic loss. In the majority of cases, these losses were more frequent in invasive tumors than in their non-invasive counterparts, suggesting these to be markers of tumor progression. Other regions showed similar frequencies of LOH in both invasive and non-invasive tumors, implying these to be early changes in pituitary tumorigenesis. This genome-wide study also revealed chromosomal regions where losses were frequently associated with an individual marker, for example, chromosome arm 1q (LOH > 30%). In some cases, these losses were subtype-specific and were found at a higher frequency in invasive tumors than in their non-invasive counterparts. Identification of these regions of loss provides the first preliminary evidence for the location of novel putative TSGs involved in pituitary tumorigenesis that are, in some cases, subtype-specific. This investigation provides an unbiased estimate of global aberrations in sporadic pituitary tumors as assessed by LOH analysis. The identification of multiple "hotspots" throughout the genome may be a reflection of an unstable chromatin structure that is susceptible to a deletion or epigenetic-mediated gene-silencing events. © 2003 Wiley-Liss, Inc. [source] Monitoring and management of the endangered Cape mountain zebra Equus zebra zebra in the Western Cape, South AfricaAFRICAN JOURNAL OF ECOLOGY, Issue 2 2008Rebecca K. Smith Abstract De Hoop Nature Reserve and a neighbouring conservancy contain the most genetically diverse subpopulation of the Endangered (IUCN) Cape mountain zebra (Equus zebra zebra Linnaeus 1758). Although vital for the long-term stability of the meta-population, the population had received limited monitoring post-1999. We summarize data obtained during a population monitoring programme established in 2005. Ninety-nine individuals were identified indicating a decline in annual population growth from 6.6% (1995,1999) to 4.5% (1999,2005). The population was male biased and the deficit of females is likely to have prevented additional breeding herd formation resulting in excess nonbreeding males. These animals are currently of limited reproductive value to the meta-population and may be contributing to the decline in reproductive potential at De Hoop by competing for limited resources. One solution may be to translocate ,excess' males to reinforce existing small populations or establish new populations with females from elsewhere provided that a minimum of 78 animals is maintained at De Hoop to limit genetic loss. Population monitoring and effective management strategies for the De Hoop population and the meta-population are vital to ensure the long-term survival of Cape mountain zebra and for the success of other species recovery programmes. Résumé De Hoop Nature Reserve et une aire de conservation voisine contiennent la sous-population la plus génétiquement variée du zèbre de montagne du Cap (Equus zebra zebra Linnaeus 1758), classé« en danger » par l'UICN. Bien que vitale pour la stabilitéà long terme de la métapopulation, cette population a été peu suivie depuis 1999. Nous avons résumé les données recueillies au cours d'un programme de monitoring de la population instauré en 2005. Quatre-vingt dix-neuf individus ont été identifiés, ce qui indique un déclin de la croissance annuelle de la population de 6,6% (1995,1999) à 4,5% (1999,2005). La population est biaisée en faveur des mâles, et c'est probablement le déficit en femelles qui a empêché la formation d'un troupeau reproducteur supplémentaire, qui a abouti à un excès de mâles nonreproducteurs. Ces animaux sont actuellement de peu de valeur de reproduction pour la métapopulation et pourraient contribuer au déclin du potentiel reproducteur à De Hoop par la compétition qu'ils représentent pour les ressources limitées.Une solution pourrait être de déplacer les mâles « en excès » pour renforcer les petites populations existantes ou pour en établir de nouvelles avec des femelles venues d'ailleurs, pour autant qu'un minimum de 78 animaux restent à De Hoop pour limiter l'appauvrissement génétique. Des stratégies pour le monitoring et la gestion efficace de la population de De Hoop sont vitales pour garantir la survie à long terme du zèbre de montagne du Cap et pour la réussite des programmes de restauration d'autres espèces. [source] Greasing the wheels of A, clearance in Alzheimer's Disease: The role of lipids and apolipoprotein EBIOFACTORS, Issue 3 2009Jianjia Fan Abstract Although apolipoprotein E (apoE) is the most common genetic risk factor for Alzheimer's Disease (AD), how apoE participates in AD pathogenesis remains incompletely understood. ApoE is also the major carrier of lipids in the brain. Here, we review studies showing that the lipidation status of apoE influences the metabolism of A, peptides, which accumulate as amyloid deposits in the neural parenchyma and cerebrovasculature. One effect of apoE is to inhibit the transport of A, across the blood-brain-barrier (BBB), particularly when apoE is lipidated. A second effect is to facilitate the proteolytic degradation of A, by neprilysin and insulin degrading enzyme (IDE), which is enhanced when apoE is lipidated. We also describe how apoE becomes lipidated and how this impacts A, metabolism. Specifically, genetic loss of the cholesterol transporter ABCA1 impairs apoE lipidation and promotes amyloid deposition in AD mouse models. ABCA1 catalyses the ATP-dependent transport of cholesterol and phospholipids from the plasma membrane to lipid-free apolipoproteins including apoE. Conversely, selective overexpression of ABCA1 increases apoE lipidation in the central nervous system (CNS) and eliminates the formation of amyloid plaques in vivo. Deficiency of Liver-X-Receptors (LXRs), transcription factors that stimulate ABCA1 and apoE expression, exacerbates AD pathogenesis in vivo, whereas treatment of AD mice with synthetic LXR agonists reduces amyloid load and improves cognitive performance. These studies provide new insights into the mechanisms by which apoE affects A, metabolism, and offer opportunities to develop novel therapeutic approaches to reduce the leading cause of dementia in the elderly. © 2009 International Union of Biochemistry and Molecular Biology, Inc. 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