Showing papers by "Alison Goate published in 1999"
TL;DR: It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.
Abstract: Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.
2,078 citations
TL;DR: This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE.
Abstract: We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of >/=65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairs where neither possessed anstraightepsilon4 allele. Sixteen peaks with a multipoint lod score (MLS) >1 either in the whole sample, the straightepsilon4-positive or -negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10 (two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulation studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfilLander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other peaks were only marginally less significant than this, in particular those on chromosomes 14 (MLS 2.16), 5 (MLS 2.00), 12, close to alpha2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77). This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE. Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neurobiological studies of AD.
382 citations
TL;DR: It is shown that PS1 aspartate mutants were indistinguishable from wild-type PS1 in their ability to bind Notch or traffic with it to the cell surface, and did not alter the secretion of Notch.
266 citations
TL;DR: Joint consideration of the DSM-IV diagnosis of alcoholism and the amplitude of the P300 component of the Cz event-related potential significantly increases the evidence for linkage of these traits to a chromosome 4 region near the class I alcohol dehydrogenase locus ADH3.
Abstract: The availability of robust quantitative biological markers that are correlated with qualitative psychiatric phenotypes can potentially improve the power of linkage methods to detect quantitative-trait loci influencing psychiatric disorders. We apply a variance-component method for joint multipoint linkage analysis of multivariate discrete and continuous traits to the extended pedigree data from the Collaborative Study on the Genetics of Alcoholism, in a bivariate analysis of qualitative alcoholism phenotypes and quantitative event-related potentials. Joint consideration of the DSM-IV diagnosis of alcoholism and the amplitude of the P300 component of the Cz event-related potential significantly increases the evidence for linkage of these traits to a chromosome 4 region near the class I alcohol dehydrogenase locus ADH3. A likelihood-ratio test for complete pleiotropy is significant, suggesting that the same quantitative-trait locus influences both risk of alcoholism and the amplitude of the P300 component.
189 citations
TL;DR: The results suggest that the genetic relationship between presenilins and the Notch signaling pathway derives from a direct physical association between these proteins in the secretory pathway.
Abstract: Genetic analyses in Caenorhabditis elegans demonstrate that sel-12 and hop-1, homologues of the Alzheimer’s disease-associated presenilin genes, modify signaling through LIN-12 and GLP-1, homologues of the Notch cell surface receptor To gain insight into the biochemical basis of this genetic interaction, we tested the possibility that presenilin-1 (PS1) physically associates with the Notch1 receptor in mammalian cells Notch1 and PS1 coimmunoprecipitated from transiently transfected human embryonic kidney 293 cell lysates in a detergent-sensitive manner, consistent with a noncovalent physical association between the two proteins The interaction predominantly occurred early in the secretory pathway prior to Notch cleavage in the Golgi, because PS1 immunoprecipitation preferentially recovered the full-length Notch1 precursor When PS1 was immunoprecipitated from 293 cells that had been metabolically labeled with [35S]methionine and [35S]cysteine, Notch1 was the primary protein detected in PS1 immunoprecipitates, suggesting that this interaction is specific Furthermore, endogenous Notch and presenilin coimmunoprecipitated from cultured Drosophila cells, indicating that physical interaction can occur at physiological expression levels These results suggest that the genetic relationship between presenilins and the Notch signaling pathway derives from a direct physical association between these proteins in the secretory pathway
177 citations
71 citations
TL;DR: Results fail to show an association between this polymorphism in the alpha2-macroglobulin gene (I1000V) and disease.
46 citations
TL;DR: Analysis of sibpairs with late onset Alzheimer's disease suggests that neither the PS1 nor the PS2 gene is a major locus for late-onset AD, but that the APP gene cannot be ruled out as a risk locus in those sibships without an E4 allele.
44 citations
TL;DR: Problem 1 of Genetic Analysis Workshop 11 consists of data from a family study of the genetics of alcoholism and related traits contributed by the six centers making up the National Institute for Alcohol Abuse and Alcoholism sponsored by the Collaborative Study on the Genetics of Alcoholism (COGA).
Abstract: Problem 1 of Genetic Analysis Workshop 11 consists of data from a family study of the genetics of alcoholism and related traits contributed by the six centers making up the National Institute for Alcohol Abuse and Alcoholism sponsored by the Collaborative Study on the Genetics of Alcoholism (COGA). The family data included 1,214 members of 105 pedigrees ascertained for having three or more individuals affected with alcoholism. Data available to workshop participants included clinical phenotypes, personality measures, smoking behavior, event-related potentials, platelet monamine oxidase B activity, and a genome scan of 296 markers.
43 citations
TL;DR: The construction of an approximately 1.7-Mb sequence-ready YAC/BAC clone contig of 8p22-p23 provides the starting point for transcription mapping, genomic sequencing, and positional cloning of this region.
25 citations
Mayo Clinic1, Erasmus University Rotterdam2, VU University Amsterdam3, University of Queensland4, Princess Alexandra Hospital5, Yeshiva University6, University of Manchester7, Oregon Health & Science University8, Mater Misericordiae Hospital9, Veterans Health Administration10, Washington University in St. Louis11
TL;DR: No evidence that the age of onset of disease was influenced by the ApoE genotype was found in a series of families with frontal temporal dementia with defined mutations in the tau gene.
TL;DR: To identify loci involved in the control of platelet monoamine oxidase B (MAO-B) activity, a genomewide linkage screen was performed using 291 markers in 148 nuclear families containing a total of 1,008 nonindependent sib-pairs to provide consistency with linkage.
Abstract: To identify loci involved in the control of platelet monoamine oxidase B (MAO-B) activity, a genomewide linkage screen was performed using 291 markers in 148 nuclear families containing a total of 1,008 nonindependent sib-pairs. Participants were genotyped and their platelet MAO-B activity levels were measured as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Sib-pair analysis using Haseman-Elston regression was carried out with two programs. Two-point analysis on all pairs with SIBPAL indicated three markers with p-values below 0.01: D6S1018 (p = 0.0004), D2S1328 (p = 0.008), and D2S408 (p = 0.003). MAPMAKER/SIBS multipoint analyses using independent pairs(N = 409) gave maximal lod scores of 2. 0 on chromosome 6 and 1.1 and 1.4 for the two regions on chromosome 2. These results are consistent with linkage, but do not provide definitive evidence. We are currently creating a denser map in these regions and have begun genotyping a second sample in COGA.
Patent•
30 Apr 1999
TL;DR: Isolated nucleic acid molecules that include a tau gene sequence are described in this paper, which have a mutation linked to a Tau pathology, and transgenic non-human mammals containing a Tau pathology are also described.
Abstract: Isolated nucleic acid molecules that include a tau gene sequence are described. The tau gene sequences have a mutation linked to a Tau pathology. Transgenic non-human mammals containing a Tau pathology are also described.
TL;DR: To characterize the FTDP-17 candidate region, flanked by the markers D17S1789 and D 17S1804, a physical map was constructed and a detailed transcript map was generated by positioning known genes and EST clusters to the physical map.