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Biomedical subjects

M Hutton

Publications and source records attributed to M Hutton.

At least 109 records · Page 6Linked to original sources
PubMed1996

Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.

Mutations in the genes encoding amyloid-beta precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid beta-protein (beta APP) processing, which normally leads to the secretion of amyloid-beta protein (relative molecular mass 4,000; M(r) 4K; approximately 90% A beta1-40, approximately 10% A beta1-42(43)), so that the extracellular concentration of A beta42(43) is increased. This increase in A beta42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because A beta42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of A beta42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain A beta42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of A beta42(43) in the brain.

Amyloid beta-Peptides↗
PubMed1996

Structure and alternative splicing of the presenilin-2 gene.

Missense mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes have been shown to be causes of autosomal dominant Alzheimer's disease (the AD3 and AD4 loci, respectively). Alternative splicing has previously been reported in the PS-1 gene. In this study, elucidation of intron/exon boundary sequences revealed that PS-2 is encoded by 10 coding exons. In addition, PS-2 cDNA cloning and RT-PCR using RNA from a variety of normal tissues revealed the presence of alternatively spliced products. These products included species with in frame omissions of exon 8 and simultaneous omissions of exons 3 and 4.

Alternative Splicing↗
PubMed1996

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease.

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimer's disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Alzheimer Disease↗
PubMed1996

Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease. Alzheimer's Disease Collaborative Group.

BACKGROUND: Mutations in the presenilin-1 (PS-1) gene are associated with early-onset Alzheimer's disease. 40-50% of the risk for late-onset disease has been attributed to alleles at the apolipoprotein E (ApoE) locus. We have looked for an association between PS-1 and late- onset disease. METHODS: We collected blood samples from 208 white cases of dementia of the Alzheimer type and from 185 age-matched controls (mean ages 76.9 and 76.2 years, respectively; 58% female in each series). Clinical diagnostic accuracy for Alzheimer's disease in our patients is 96%. We also studied 29 African-American patients with dementia of the Alzheimer type and 50 age-matched controls (cases vs controls, 77.2 vs 72.0 years; 72 vs 77% female). We used PCR to test for an association between Alzheimer's disease and a polymorphism within the intron 3' to exon 8 of the PS-1 gene. The ApoE genotype of most of the cases and controls was known from previous investigations. FINDINGS: Homozygosity of the 1 allele in the PS-1 gene was associated with a doubling of the risk for late-onset Alzheimer's disease compared with the [12]/[22] genotype (odds ratio 1.97, 95% Cl 1.29-3.00). The proportion of Alzheimer's disease cases in the white population that could be attributed to homozygosity at this locus, as estimated by the attributable fraction, was 0.22. This compares with 0.35 for a single copy of ApoE4 and 0.15 for two copies. The smaller African-American series showed similar distribution of PS-1 genotype between cases and controls. INTERPRETATION: In our white series of cases, PS-1 accounted for about half as much of the risk for late-onset Alzheimer's disease as did ApoE4.

Age Factors↗
PubMed1996

Polymorphism in AACT gene may lower age of onset of Alzheimer's disease.

The ApoE-epsilon 4 allele is a predisposing factor for late onset Alzheimer's disease (AD), however it is neither necessary nor sufficient to cause the disease. A candidate for explaining part of the remaining genetic component is alpha 1-antichymotrypsin (AACT). In a case-control study we genotyped a polymorphism within the AACT gene to test for association with the disease. No allele of this gene showed an increased incidence among the population with AD compared with controls, even when taking ApoE genotype into account. This contrasts with the results of a recently published report. The mean age of onset was apparently lowered by the presence of the AACT AA genotype among ApoE-epsilon 4 bearers. If AACT genotype has an effect on risk for AD it may be predominantly amongst individuals with early onset AD.

Age of Onset↗
PubMed1996

Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer's disease: predominance of Abeta42(43).

Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 8 cases of (genetically confirmed) chromosome 14-linked Alzheimer's disease (AD) using the end-specific monoclonal antibodies BA27 and BC05 to detect the presence of Abeta40 and Abeta42(43), respectively. In all patients, Abeta42(43) was the predominant peptide species present. The total amount of Abeta40 and Abeta42(43) deposited was more than twice the amount deposited in cases of sporadic AD of similar disease duration, although the ratio between the extent of Abeta40 and Abeta42(43) deposition was unaltered, compared with sporadic AD. Therefore, (one of) the effects of the mutations in the presenilin 1:PS-1 (S182) gene may be to cause or at least promote an early and excessive deposition of Abeta42(43) within the brain, a property shared with other inherited forms of AD, such as those due to amyloid precursor protein mutations, and Down's syndrome (trisomy 21).

Adult↗
PubMed1996

A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease.

Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease. Here we describe a further mutation in the presenilin 1 gene (R269G) in a family with early onset Alzheimer's disease. This mutation is in exon 8 which appears to be a favoured region for pathogenic mutations. In the presenilin protein the region coded for by this exon is likely to comprise a domain located on the membrane surface. We discuss the likely effects of the exon 8 mutations on the structure of the exon and in the pathogenesis of the disease.

Alzheimer Disease↗
PubMed1996

Alteration in brain presenilin 1 mRNA expression in early onset familial Alzheimer's disease.

The expression of the presenilin 1 (PS-1) gene has been investigated by in situ hybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14-linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. The in situ hybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS-1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5' end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.

Adult↗
PubMed1996

Presenilin-1 is processed into two major cleavage products in neuronal cell lines.

Presenilin-1 (PS-1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). Using PS-1 transfected SHSY5Y neuroblastoma cells, we have demonstrated by immunodetection, using polyclonal antibodies, that PS-1 is processed to give two fragments: an N-terminal 28 kDa fragment, and a C-terminal 18 kDa fragment. In a number of non-transfected cell types, most PS-1 is detected as the cleaved products. The molecular weights of the PS-1 cleavage products suggest that the cleavage point will most probably be within a region of the hydrophilic loop domain coded for by either exon 8 or 9 of the PS-1 gene. The clustering of FAD mutations within exon 8 strongly suggests that it encodes a key functional domain. It seems likely that the cleavage of PS-1 is crucial to some aspect of its functionality. An understanding of this process will give insights into the pathology of AD, and may offer new opportunities for therapeutic intervention.

Amino Acid Sequence↗
PubMed1996

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Alzheimer Disease↗
PubMed1996

Secondary prevention of cancer.

In recent years prevention has become extremely important in the war against cancer. For many cancers, major risk factors are not amenable to change and, therefore, secondary prevention through screening and early detection is the major type of intervention. Furthermore, with the discovery of cancer genes and tumor markers, which make it easier than ever before to identify people with increased risk of developing certain types of cancers, the role of secondary prevention has assumed an even greater value. This paper reviews recent advances in secondary prevention of those cancers for which overall efficacy of screening to reduce mortality has been demonstrated but for which some residual controversies exist: breast, cervical, and colorectal cancers.

Breast Neoplasms↗
PubMed1996

The association between occupation and tuberculosis. A population-based survey.

There has been increasing interest in the potential association between occupation and the risk of tuberculosis. Therefore, we analyzed occupational information collected on all patients with clinically active tuberculosis in 29 states from 1984 to 1985. Census data were used to estimate the number of persons in each of the occupations. Information on employment and occupation was ascertained for 9,534 (99%) of the working age (16 through 64 yr) tuberculosis patients. The overall case rate of tuberculosis in this age group in the study areas was 8.4 per 100,000 persons, which was slightly lower than the national rate of 9.3 per 100,000 persons. As a group, health care workers had rates of tuberculosis similar to the general population (standardized morbidity ratio [SMR]: 1.0; 95% CI: 0.9 to 1.1). However, elevated rates were observed for inhalation therapists (SMR: 2.9; 95% CI: 1.2 to 6.0), and lower-paid health care workers (SMR: 1.3; 95% CI: 1.1 to 1.5). Elevated rates were also noted for funeral directors (SMR: 3.9; 95% CI: 2.2 to 6.1) and farm workers (SMR: 3.7; 95% CI: 3.4 to 4.1). These data suggest that even in communities with relatively low rates of tuberculosis certain occupations may be associated with an elevated risk.

Adolescent↗
PubMed1996

The role of presenilin 1 in the genetics of Alzheimer's disease.

Approximately 75% of AD patients have an onset of the disease after the age of 60 years, and 60% of AD patients have no family history of the disease. Some cases of EOAD are clearly inherited in an autosomal-dominant manner. The beta APP gene on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 have all been characterized as genes in which mutations lead to familial EOAD. For LOAD, the work on ApoE indicates that the epsilon 4 allele is a risk factor for developing AD. However, 35-50% of all AD patients do not have an epsilon 4 allele. Other loci contributing to LOAD remain to be mapped and characterized. As in other complex disorders, these additional loci may involve genetic interactions with the known AD loci. Identification of all susceptibility loci for AD is a major goal in resolving the pathogenesis of AD.

Alternative Splicing↗
PubMed1995

The involvement of NADP(H) binding and release in energy transduction by proton-translocating nicotinamide nucleotide transhydrogenase from Escherichia coli.

Proton-translocating transhydrogenase was solubilised and purified from membranes of Escherichia coli. Consistent with recent evidence [Hutton, M., Day, J., Bizouarn, T. and Jackson, J.B. (1994) Eur. J. Biochem. 219, 1041-1051], at low pH and salt concentration, the enzyme catalysed rapid reduction of the NAD+ analogue AcPdAD+ by a combination of NADH and NADPH. At saturating concentrations of NADPH, the dependence of the steady-state rate on the concentrations of NADH and AcPdAD+ indicated that, with respect to these two nucleotides, the reaction proceeds by a ping-pong mechanism. High concentrations of either NADH or AcPdAD+ led to substrate inhibition. These observations support the view that, in this reaction, NADP(H) remains bound to the enzyme: AcPdAD+ is reduced by enzyme-bound NADPH, and NADH is oxidised by enzyme-bound NADP+, in a cyclic process. When this reaction was carried out with [4A-2H]NADH replacing [4A-1H]NADH, the rate was decreased by 46%, suggesting that the H- transfer steps are rate-limiting. In simple 'reverse' transhydrogenation, the reduction of AcPdAD+ was slower with [4B-2H]NADPH than with [4B-1H]NADPH when the reaction was performed at pH 8.0, but there was no deuterium isotope effect at pH 6.0. This indicates that H- transfer is rate-limiting at pH 8.0 and supports our earlier suggestion that NADP+ release from the enzyme is rate-limiting at low pH. The lack of a deuterium isotope effect in the reduction of thio-NADP+ by NADH at low pH is also consistent with the view that NADPH release from the enzyme is slow under these conditions. A steady-state rate equation is derived for the reduction of AcPdAD+ by NADPH plus NADH, assuming operation of the cyclic pathway. It adequately accounts for the pH dependence of the enzyme, for the features described above and for kinetic characteristics of E. coli transhydrogenase described in the literature.

Escherichia coli↗
PubMed1995

Properties of the soluble polypeptide of the proton-translocating transhydrogenase from Rhodospirillum rubrum obtained by expression in Escherichia coli.

Transhydrogenase, which catalyses the reduction of NADP+ by NADH coupled to proton translocation across a membrane, may be unique in the photosynthetic bacterium Rhodospirillum rubrum. Unlike the homologous enzyme from animal mitochondria and other bacterial sources, it has a water-soluble polypeptide, which exists as a dimer (Ths), that can be reversibly dissociated from the membrane component [Williams, R., Cotton, N. P. J., Thomas, C. M. & Jackson, J. B. (1994) Microbiology, 140, 1595-1604]. We have expressed the gene for Ths in cells of Escherichia coli under control of the tac promoter and a strong ribosome binding site. The protein, purified by column chromatography, fully reconstituted transhydrogenation activity to everted membrane vesicles of Rhs. rubrum that had been washed to remove Ths. The purified expressed protein was prepared in quantities over 100-fold greater than were obtained from wild-type Rhs. rubrum. The fluorescence spectrum of purified expressed Ths had an intense and unusually short wavelength emission maximum at 310 nm with shoulders at 298 and 322 nm. Time-resolved measurements indicated that the fluorescence decay was almost monoexponential with a lifetime of 5.2 ns. On denaturation with 4 M guanidine hydrochloride, the emission band shifted to 352 nm and decreased in intensity. In the native protein, the fluorophore was relatively inaccessible to quenching solutes, such as iodide ions and acrylamide. It is concluded that the fluorescence emission arises mainly from the single tryptophan residue of Ths (Trp72), which is locked into a rigid conformation and is located in highly non-polar environment. The 310-nm fluorescence of Ths was quenched by NADH, maximally to 46%. The apparent binding constant was 18 microM. The fluorescence of Ths-bound NADH was enhanced relative to the nucleotide in free solution and its emission maximum was shifted to a shorter wavelength (440 nm). These data support previous indications that the NADH binding site is located in domain I of proton-translocating transhydrogenase. Excitation of Ths at 280 nm did not lead to sensitized emission at 440 nm from bound NADH. This indicates that the quenching of fluorescence of Ths by NADH does not result from resonance energy transfer from Trp72 to the bound nucleotide. NAD+, NADP+ and NADPH had little effect on the protein fluorescence. The kinetics of quenching of Ths fluorescence by NADH were examined after mixing in a stopped-flow device. The 'on' rate constant for nucleotide binding was approximately 8 x 10(6) M-1 s-1 and the 'off' constant approximately 150 s-1.

Amino Acid Sequence↗
PubMed1995

Butyrate metabolism in the terminal ileal mucosa of patients with ulcerative colitis.

The rate of oxidation of butyrate, glutamine and glucose was investigated in terminal ileal mucosal biopsy samples from nine patients with ulcerative colitis undergoing restorative proctocolectomy and from 12 patients undergoing laparotomy for reasons other than ulcerative colitis. Substrate oxidation was assayed using a radiolabelled isotope technique. Butyrate was the preferred fuel substrate, followed by glutamine and then glucose (median (95 per cent confidence interval) 567 (262-894), 63 (35-123) and 8.1 (5.1-18) pmol micrograms-1 h-1 respectively; P < 0.01, Mann-Whitney U test) in normal terminal ileal mucosa. The patients with ulcerative colitis had a significantly reduced rate of butyrate oxidation compared with the control group (194 (81-321) versus 567 (262-894) pmol micrograms-1 h-1, P < 0.05). Normal terminal ileal mucosa oxidized butyrate in greater quantities than glucose and glutamine. Ulcerative colitic terminal ileal mucosa exhibited an impaired rate of butyrate oxidation.

Adolescent↗