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M C Chartier-Harlin

Publications and source records attributed to M C Chartier-Harlin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Synthesis of apolipoprotein E (ApoE) mRNA by human neuronal-type SK N SH-SY 5Y cells and its regulation by nerve growth factor and ApoE.

By in situ hybridization, we show the ability of human neuroblastoma SY 5Y cells to synthesize apolipoprotein E (apoE) mRNA. This synthesis varied during cell NGF-differentiation: the mRNA level decreased during the first 4 days of NGF treatment (NGF 4 days) and then increased during the 3 following days (NGF 7 days). Furthermore, a treatment of 4-day NGF differentiated cells with exogenous apoE during 3 additional days induced a clear decrease in apoE mRNA synthesis when compared with control cells. This effect was more or less pronounced according to the apoE tested variants: apoE4 was more efficient to decrease the apoE mRNA synthesis as compared with the control cells than apoE3 which was itself more efficient than apoE2. These results suggest that apoE mRNA synthesis in human neuronal-type cells could be regulated by different mechanisms such as those induced by NGF- and apoE-treatments.

Apolipoproteins E↗
PubMed1999

No association between the alpha-2 macroglobulin I1000V polymorphism and Alzheimer's disease.

Recent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.

Age of Onset↗
PubMed1999

A new GTP-cyclohydrolase I mutation in an unusual dopa-responsive dystonia, familial form.

We found a new mutation in the GTP cyclohydrolase gene involved in dopa-responsive dystonia. We sequenced the GTP cyclohydrolase gene in a family with four siblings affected by this disorder and identified an A-T mutation in exon 2, leading to a non conservative amino acid substitution at codon 135 of the protein (Ile135Lys), which may change the conformation of the binding site of this enzyme. The clinical evolution was heterogeneous among carriers of the same mutation, underlining the involvement of other determinants modulating the occurrence of the disease such as genetic or environmental susceptibility factors.

Adolescent↗
PubMed1999

No pathogenic mutations in the persyn gene in Parkinson's disease.

The persyn (gamma-synuclein) gene is highly homologous to the alpha-synuclein gene and is highly expressed in the nervous system. It is therefore, an excellent candidate gene for Parkinson's disease. However, we have sequenced the gene in a large number of families with parkinsonism and failed to find pathogenic mutations.

Age of Onset↗
PubMed1999

Association between coding variability in the LRP gene and the risk of late-onset Alzheimer's disease.

We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12 cases of Alzheimer's disease (AD) from Northern France. We have found no novel changes but confirm the occurrence of a polymorphism in exon 6 of the gene (A216V). This polymorphism is rare (2.8% of controls) and is in linkage equilibrium with previously reported polymorphisms. The V216 allele is negatively associated with the disease in a large case-controlled series. These data suggest that the LRP receptor may be involved in the pathobiology of AD, but the association that we report here cannot explain the previously reported genetic data implicating the LRP gene in AD. If the LRP gene is a major site of genetic variability leading to AD, there must be other biologically relevant variability in promoter or other regulatory elements of this large gene.

Aged↗
PubMed1999

Is the LDL receptor-related protein involved in Alzheimer's disease?

LDL-related protein receptor (LRP) is the main receptor in the brain for apolipoprotein E. Moreover, the LRP gene is located on chromosome 12, the site of a potential Alzheimer's disease (AD) locus. We explored the association between the LRP gene and AD in 600 French Caucasian patients (37.8% men, mean age 72.0+/-8.0 years, mean age at onset 68.7+/-8.1 years) and age-matched controls (n=646, 37.0% men, mean age 72.5+/-8.2 years) and observed an association between a (TTTC) repeat at the 3' end of an Alu sequence in the LRP gene and the risk of developing AD. Three alleles were detected in this population [corresponding to 83, 87, and 91 base pairs (bp)], the 91-bp allele being associated with an increased risk of developing AD [all patients: odds ratio (OR) 1.6, P<0.01; late-onset AD: OR 1.8, P<0.01]. This suggests an association between the LRP locus and AD. However, in the light of studies related to the exon 3 LRP polymorphism and given the low strength of the association reported here, a biologically active variant may exist on chromosome 12, either in the LRP gene itself or in another gene in the vicinity.

Age of Onset↗
PubMed1999

A novel presenilin-2 splice variant in human Alzheimer's disease brain tissue.

Mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes account for the majority of cases of early-onset familial Alzheimer's disease (AD). Alternative splicing forms of the PS-1 and PS-2 gene products have previously been reported in fibroblast and brain tissue from both familial and sporadic AD patients, as well as from normal tissues and cell lines. We demonstrate here unusual alternative splicing of the PS-2 gene that leads to the generation of mRNA lacking exon 5 in human brain tissue. This product was more frequently detected in brain tissue from sporadic AD patients (70.0%; 21 of 30) than from normal age-matched controls (17.6%; three of 17). In cultured neuroblastoma cells, this splice variant was generated in hypoxia but not under other forms of cellular stress. Hypoxia-mediated induction of this splice variant was blocked by pretreatment of neuroblastoma cells with the protein synthesis inhibitor cycloheximide or antioxidants such as N-acetylcysteine and diphenyl iodonium, suggesting that hypoxia-mediated oxidant stress might, at least in part, underlie the alternative splicing of PS-2 mRNA through de novo protein synthesis. Furthermore, the stable transfectants of this splice variant produced the N-terminal part of PS-2 protein (15 kDa) and were more susceptible to cellular stresses than control transfectants. These results suggest the possibility that altered presenilin gene products in stress conditions may also participate in the pathogenesis of AD.

Aged↗
PubMed1999

A full genome scan for late onset Alzheimer's disease.

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.

Age of Onset↗
PubMed1998

Genetic studies on chromosome 12 in late-onset Alzheimer disease.

CONTEXT: The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report has suggested a second locus on chromosome 12p11-12. OBJECTIVE: To look for evidence of linkage on chromosome 12 and to test for the presence of the new locus in an independent sample of familial late-onset AD cases. DESIGN: Retrospective cohort study. As part of a 20-centimorgan genome screen (approximately equal to 200 markers), we tested a series of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. SETTING: Clinic populations in the continental United States selected from the National Institute of Mental Health AD Genetics Consortium. PATIENTS: We selected samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable or definite AD with onset ages older than 60 years (mean+/-SD, 75+/-6 years). Within the families, we used the 2 probable or definitely affected individuals. In families with more than 2 such cases available, we used all of them; in families with only 2 such cases in which unaffected individuals were available, we also sampled the oldest unaffected individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. MAIN OUTCOME MEASURE: Presence of linkage or locus on chromosome 12. RESULTS: Although linkage analyses confirmed the presence of a genetic susceptibility factor at the APOE locus in these families with late-onset AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the alpha2-macroglobulin locus in the affected pairs in which both members did not possess an APOE epsilon4 allele. CONCLUSIONS: APOE remains the only locus established to be a risk factor for late-onset AD. We were unable to confirm that a locus on chromosome 12p11-12 has a major effect on risk for late-onset AD, although an effect smaller than that for APOE cannot be excluded.

Age of Onset↗
PubMed1998

A new polymorphism in the APOE promoter associated with risk of developing Alzheimer's disease.

The epsilon4 allele of the Apolipoprotein E gene (APOE), one of the main allele of APOE polymorphism, is a major risk factor for the development of Alzheimer's disease. However, several data suggest that genetic factors, within the APOE locus, may also modulate the risk associated with this polymorphism. We look for new mutations in the APOE promoter, susceptible to modify the risk associated with the APOE epsilon4 allele. We characterised a G-->T mutation at -186 bp of the APOE gene TATA box, named Th1/E47cs. This new polymorphism is located in a consensus sequence of a potential transcriptional (Th1/E47) factor binding site. We studied the impact of this new polymorphism with those of other markers of the APOE locus in a large case-control study and observed that Th1/E47cs modulated the influence of the APOE epsilon4 allele on the risk of Alzheimer's disease.

Aged↗
PubMed1998

Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease.

Possession of the apolipoprotein E (APOE) epsilon4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's disease (AD). Recently, new polymorphisms in the regulatory region of the APOE gene have been described. We analysed the effects of three of these mutations (-491 AT, -427 CT and Th1/E47cs) on disease risk in a large case-control study, and tested their impacts on APOE allelic expression in brain tissues. The Th1/E47cs T allele was associated with an increased risk of occurrence of AD, while the -491 T allele was associated with a decreased risk, independently of the APOE epsilon2/epsilon3/epsilon4 polymorphism effect. However, the impact of the Th1/E47cs mutation was the strongest. The -427 CT polymorphism was not associated with the disease. In AD subjects heterozygous for the epsilon4 allele, analysis of allelic expression showed that the relative expression levels of the epsilon4 allele were higher than those of the corresponding controls. Consistent with epidemiological data, the relative level of expression of the epsilon4 allele was modified accordingly to the presence or absence of the two main promoter polymorphisms, indicating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population. These data indicate that in addition to the qualitative effect of the APOE epsilon2/epsilon3/epsilon4 polymorphisms on the AD occurrence, the quantitative variation of expression of these alleles due to functional APOE promoter mutations, is a key determinant of AD development.

Aged↗
PubMed1997

Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people. It usually occurs after 65 years old (late-onset AD). The epsilon4 allele of apolipoprotein E (APOE) gene is a risk factor which contributes about 50% of the genetic risk for this form of the disease. The low density lipoprotein receptor-related protein (LRP) is a major receptor for APOE which is found in the senile plaques of AD brains. This makes it a good candidate gene for the disease. There is a polymorphism in the region upstream of the LRP gene that has been associated with AD in an American population. We examined this polymorphism by restriction fragment length polymorphism analysis in a French population with sporadic late-onset AD. In the previous report, a significant increase of the 87 bp allele was found in the AD cases; however, in our population, we observed a significant decrease with this same allele of the LRP gene. The possible reasons for this discrepancy, linkage disequilibrium or statistical anomaly, are discussed.

Age of Onset↗
PubMed1997

ApoE synthesis in human neuroblastoma cells.

Apolipoprotein E (apoE) is associated with the two hallmarks of Alzheimer's disease: A beta deposits and neurofibrillary tangles. ApoE synthesis was detected in astrocytes by in situ hybridization but was not detected in neurons. Nevertheless, different studies on apoE immunoreactivity reported the presence of apoE in neurons of Alzheimer, control, and necrosis pontisubicular brains. In this study, we addressed the question of potential synthesis of apoE in neurons and its possible involvement in or in response to pathological conditions. To this purpose, we have studied human neuronal cell lines (SY 5Y and Kelly cells) originating from neuroblastoma. Using monoclonal and polyclonal antibodies, a 32-kDa band was detected in SY 5Y and Kelly cells, before and after NGF differentiation. Two-dimensional gel electrophoresis analysis showed a typical profile of apoE spots resolved to the exact isoelectric points. By reverse transcription-polymerase chain reaction experiments, we demonstrated the presence of apoE mRNA in these cell lines. SY 5Y cells synthesized the apoE3 variant, whereas Kelly cells expressed both apoE3 and apoE4 isoforms, corroborating the two-dimensional gel results. These results suggested that apoE synthesis could occur in human neuronal cell lines under certain conditions.

Antibodies, Monoclonal↗
PubMed1997

Distortion of allelic expression of apolipoprotein E in Alzheimer's disease.

The APOE epsilon4 allele is a strong genetic susceptibility factor for Alzheimer's disease. Interaction with other biological factors may modulate the effect of the apoE isoforms. However, previous work suggested that other genetic variability within the APOE locus, influencing the effect of the epsilon4 allele, may exist. Such variability could modify the expression of the APOE gene and, in particular, the level of expression of APOE alleles could be an important determinant of disease pathogenesis. To test this hypothesis we examined the levels of expression of APOE in heterozygotes with AD and in controls, using a new method of semi-quantitation. We report that relative epsilon4 mRNA expression is increased in AD compared with controls and suggest that genetic variability in the neural expression of APOE contributes to disease risk.

Aged↗
PubMed1997

Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex.

The distribution of apolipoprotein E (APOE) genotypes as a function of age and sex has been examined in a French population of 417 Alzheimer disease (AD) patients and 1,030 control subjects. When compared to the APOE epsilon3 allele, an increased risk associated with the APOE epsilon4 allele (odds ratio [OR] [epsilon4] = 2.7 with 95% confidence interval [CI] = 2.0-3.6; P < .001) and a protective effect of the APOE epsilon2 allele (OR[epsilon2] = 0.5 with 95% CI = 0.3-0.98; P = .012) were retrieved. An effect of the epsilon4 allele dosage on susceptibility was confirmed (OR[epsilon4/epsilon4] vs. the epsilon3/epsilon3 genotype = 11.2 [95% CI = 4.0-31.6]; OR[epsilon3/epsilon4] vs. the epsilon3/epsilon3 genotype = 2.2 [95% CI = 1.5-3.5]). The frequency of the epsilon4 allele was lower in male cases than in female cases, but, since a similar difference was found in controls, this does not lead to a difference in OR between sex. ORs for the epsilon4 allele versus the epsilon3 allele, OR(epsilon4), were not equal in all age classes: OR(epsilon4) in the extreme groups with onset at < 60 years or > 79 years were significantly lower than those from the age groups 60-79 years. In epsilon3/epsilon4 individuals, sex-specific lifetime risk estimates by age 85 years (i.e., sex-specific penetrances by age 85 years) were 0.14 (95% CI 0.04-0.30) for men and 0.17 (95% CI 0.09-0.28) for women.

Age of Onset↗
PubMed1996

Analysis of the APOE alleles impact in Down's syndrome.

Down's syndrome (DS) patients develop the characteristic features of Alzheimer's disease (AD) by their fourth decade, some of them exhibiting an AD-type dementia. We studied the apolipoprotein E (APOE) allele distribution in a population of 41 DS patients comprising 19.5% of demented, compared to 35 control subjects. No statistical difference was observed, but the epsilon2 allele may delay the age of dementia. As described in other studies, the impact of the different APOE alleles in DS is modest. However the compilation of all published studies on AD-type dementia in DS suggests that the epsilon2 allele has a protective effect. In delaying the age of onset, the epsilon2 allele would have a similar action in AD-type dementia in DS and in AD families with amyloid precursor protein (APP) mutations.

Aged↗