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M R Hayden

Publications and source records attributed to M R Hayden.

At least 73 records · Page 4Linked to original sources
PubMed2000

Cholesterol efflux regulatory protein, Tangier disease and familial high-density lipoprotein deficiency.

Cellular cholesterol efflux, by which cholesterol is transported from peripheral cells to HDL acceptor molecules for transport to the liver, is the first step of reverse cholesterol transport. Two genetic disorders, Tangier disease and some cases of familial HDL deficiency, have defects of cellular cholesterol efflux. The recent discovery of mutations in the ABC1 gene, which encodes the cholesterol efflux regulatory protein, in both these disorders establishes cholesterol efflux regulatory protein as a rate-limiting factor in reverse cholesterol transport.

ATP Binding Cassette Transporter 1↗
PubMed2000

Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes.

We and others have recently identified mutations in the ABCA1 gene as the underlying cause of Tangier disease (TD) and of a dominantly inherited form of familial hypoalphalipoproteinemia (FHA) associated with reduced cholesterol efflux. We have now identified 13 ABCA1 mutations in 11 families (five TD, six FHA) and have examined the phenotypes of 77 individuals heterozygous for mutations in the ABCA1 gene. ABCA1 heterozygotes have decreased HDL cholesterol (HDL-C) and increased triglycerides. Age is an important modifier of the phenotype in heterozygotes, with a higher proportion of heterozygotes aged 30-70 years having HDL-C greater than the fifth percentile for age and sex compared with carriers less than 30 years of age. Levels of cholesterol efflux are highly correlated with HDL-C levels, accounting for 82% of its variation. Each 8% change in ABCA1-mediated efflux is predicted to be associated with a 0.1 mmol/l change in HDL-C. ABCA1 heterozygotes display a greater than threefold increase in the frequency of coronary artery disease (CAD), with earlier onset than unaffected family members. CAD is more frequent in those heterozygotes with lower cholesterol efflux values. These data provide direct evidence that impairment of cholesterol efflux and consequently reverse cholesterol transport is associated with reduced plasma HDL-C levels and increased risk of CAD.

ATP Binding Cassette Transporter 1↗
PubMed2000

Familial aggregation of psychotic symptoms in Huntington's disease.

OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.

Adolescent↗
PubMed2000

Remodeling of the endocrine pancreas: the central role of amylin and insulin resistance.

BACKGROUND: Remodeling of the endocrine pancreas, caused by the deleterious effects of amylin as it is co-synthesized, co-packaged, and co-secreted with insulin, gives clinicians and researchers cause to ponder. METHODS: A literature search was done, and relevant publications and texts on amylin and islet amyloid polypeptide (IAPP) were reviewed. RESULTS: The mechanisms and clinical consequences attributed to the remodeling of the endocrine pancreas, along with proposals for reevaluating the methods of treating patients who have type 2 diabetes are illustrated and discussed. CONCLUSIONS: In addition to controlling the devastating effects ofglucotoxicity, lipotoxicity, and hypertension, we should consider the newer hypoglycemic agents with regard to their effects on the remodeling of the endocrine pancreas. This remodeling results in structural and subsequent functional changes, causing continued elevations of hemoglobin A1C. Studies are indicated to determine whether amylin (IAPP) may be implicated in the remodeling of the arterial vessel wall, the glomerulus of the kidney, and the cardiac interstitium.

Administration, Oral↗
PubMed2000

Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis.

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG);-low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL(+/-)E(-/-)) was associated with increased TG and increased total cholesterol (TC) compared with LPL(+/+)E(-/-) sibs. However despite their dyslipidemia, LPL(+/-)E(-/-) mice had significantly reduced lesion areas compared to the LPL(+/+)E(-/-) mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL(+/+)E(-/-) mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis. Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic).

Animals↗
PubMed1999

An actin-binding protein of the Sla2/Huntingtin interacting protein 1 family is a novel component of clathrin-coated pits and vesicles.

The actin cytoskeleton has been implicated in endocytosis, yet few molecules that link these systems have been identified. Here, we have cloned and characterized mHip1R, a protein that is closely related to huntingtin interacting protein 1 (Hip1). These two proteins are mammalian homologues of Sla2p, an actin binding protein important for actin organization and endocytosis in yeast. Sequence alignments and secondary structure predictions verified that mHip1R belongs to the Sla2 protein family. Thus, mHip1R contains an NH(2)-terminal domain homologous to that implicated in Sla2p's endocytic function, three predicted coiled-coils, a leucine zipper, and a talin-like actin-binding domain at the COOH terminus. The talin-like domain of mHip1R binds to F-actin in vitro and colocalizes with F-actin in vivo, indicating that this activity has been conserved from yeast to mammals. mHip1R shows a punctate immunolocalization and is enriched at the cell cortex and in the perinuclear region. We concluded that the cortical localization represents endocytic compartments, because mHip1R colocalizes with clathrin, AP-2, and endocytosed transferrin, and because mHip1R fractionates biochemically with clathrin-coated vesicles. Time-lapse video microscopy of mHip1R-green fluorescence protein (GFP) revealed a blinking behavior similar to that reported for GFP-clathrin, and an actin-dependent inward movement of punctate structures from the cell periphery. These data show that mHip1R is a component of clathrin-coated pits and vesicles and suggest that it might link the endocytic machinery to the actin cytoskeleton.

3T3 Cells↗
PubMed1999

Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux.

BACKGROUND: A low concentration of HDL cholesterol is the most common lipoprotein abnormality in patients with premature atherosclerosis. We have shown that Tangier disease, a rare and severe form of HDL deficiency characterised by a biochemical defect in cellular cholesterol efflux, is caused by mutations in the ATP-binding-cassette (ABC1) gene. This gene codes for the cholesterol-efflux regulatory protein (CERP). We investigated the presence of mutations in this gene in patients with familial HDL deficiency. METHODS: Three French-Canadian families and one Dutch family with familial HDL deficiency were studied. Fibroblasts from the proband of each family were defective in cellular cholesterol efflux. Genomic DNA of each proband was used for mutation detection with primers flanking each exon of the ABC1 gene, and for sequencing of the entire coding region of the gene. PCR and restriction-fragment length polymorphism assays specific to each mutation were used to investigate segregation of the mutation in each family, and to test for absence of the mutation in DNA from normal controls. FINDINGS: A different mutation was detected in ABC1 in each family studied. Each mutation either created a stop codon predicted to result in truncation of CERP, or altered a conserved aminoacid residue. Each mutation segregated with low concentrations of HDL-cholesterol in the family, and was not observed in more than 500 control chromosomes tested. INTERPRETATION: These data show that mutations in ABC1 are the major cause of familial HDL deficiency associated with defective cholesterol efflux, and that CERP has an essential role in the formation of HDL. Our findings highlight the potential of modulation of ABC1 as a new route for increasing HDL concentrations.

ATP Binding Cassette Transporter 1↗
PubMed1999

Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial.

OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.

Adult↗
PubMed1999

Evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease in cell culture and in transgenic mice expressing mutant huntingtin.

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with findings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These findings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.

Animals↗
PubMed1999

Cleavage of atrophin-1 at caspase site aspartic acid 109 modulates cytotoxicity.

Dentatorubropallidoluysian atrophy (DRPLA) is one of eight autosomal dominant neurodegenerative disorders characterized by an abnormal CAG repeat expansion which results in the expression of a protein with a polyglutamine stretch of excessive length. We have reported recently that four of the gene products (huntingtin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) associated with these open reading frame triplet repeat expansions are substrates for the cysteine protease cell death executioners, the caspases. This led us to hypothesize that caspase cleavage of these proteins may represent a common step in the pathogenesis of each of these four neurodegenerative diseases. Here we present evidence that caspase cleavage of atrophin-1 modulates cytotoxicity and aggregate formation. Cleavage of atrophin-1 at Asp109 by caspases is critical for cytotoxicity because a mutant atrophin-1 that is resistant to caspase cleavage is associated with significantly decreased toxicity. Further, the altered cellular localization within the nucleus and aggregate formation associated with the expanded form of atrophin-1 are completely suppressed by mutation of the caspase cleavage site at Asp109. These results provide support for the toxic fragment hypothesis whereby cleavage of atrophin-1 by caspases may be an important step in the pathogenesis of DRPLA. Therefore, inhibiting caspase cleavage of the polyglutamine-containing proteins may be a feasible therapeutic strategy to prevent cell death.

Amino Acid Sequence↗
PubMed1999

Neuronal degeneration in the basal ganglia and loss of pallido-subthalamic synapses in mice with targeted disruption of the Huntington's disease gene.

Huntington's disease (HD) is a progressive neurodegenerative disorder associated with CAG repeat expansion within a novel gene (IT15). We have previously created a targeted disruption in exon 5 of Hdh (Hdhex5), the murine homologue of the HD gene. Homozygotes for the Hdhex5 mutation exhibit embryolethality before embryonic day 8.5, while heterozygotes survive to adulthood and display increased motor activity and cognitive deficits. Detailed morphometric and stereological analyses of the basal ganglia in adult heterozygous mice were performed by light and electron microscopy. Morphometric analyses demonstrated a significant loss of neurons from both the globus pallidus (29%) and the subthalamic nucleus (51%), with a normal complement of neurons in the caudate-putamen and substantia nigra. The ultrastructural appearance of sporadic degenerating neurons in these regions indicated apoptosis. The highest frequency of apoptotic neurons was observed in the globus pallidus and subthalamic nucleus. Stereological analyses in the subthalamic nucleus revealed a significant decrease in the numerical density of symmetric synapses (43%), suggesting a relatively selective loss of inhibitory pallido-subthalamic afferents. Immunohistochemistry using antibodies against enkephalin and substance-P was unremarkable in heterozygotes, indicating a normal complement of enkephalin-immunoreactive striatopallidal afferents and substance-P-immunoreactive striatopeduncular and striatonigral afferents in these animals. These findings show that loss of an intact huntingtin protein is associated with significant morphological alterations in the basal ganglia of adult mice, indicating an important role for this protein during development of the central nervous system.

Afferent Pathways↗
PubMed1999

A yeast artificial chromosome-based physical map of the juvenile amyotrophic lateral sclerosis (ALS2) critical region on human chromosome 2q33-q34.

The autosomal recessive form of juvenile amyotrophic lateral sclerosis (ALS2; RFALS Type 3) has previously been mapped to the 8-cM interval flanked by D2S115 and D2S155 on human chromosome 2q33-q34. We have established a yeast artificial chromosome (YAC) contig spanning an approximately 8-Mb region of the ALS2 candidate region and mapped 52 transcribed DNA sequences including 13 known genes and 39 expressed sequenced tags within this YAC contig. The establishment of a YAC contig and transcript map that spans the region containing the ALS2 mutation is an essential step in the identification of the ALS2 gene.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Forskolin and dopamine D1 receptor activation increase huntingtin's association with endosomes in immortalized neuronal cells of striatal origin.

Huntingtin is a cytoplasmic protein of unknown function that associates with vesicle membranes and microtubules. Its protein interactions suggest that huntingtin has a role in endocytosis and organelle transport. In this study we sought to identify factors that regulate the transport of huntingtin in striatal neurons, which are the cells most affected in Huntington's disease. In clonal striatal cells derived from fusions of neuroblastoma and embryonic striatal neurons, huntingtin localization is diffuse and slightly punctate in the cytoplasm. When these neurons were differentiated by treatment with forskolin, huntingtin redistributed to perinuclear regions, discrete puncta along plasma membranes, and branch points and terminal growth cones in neurites. Huntingtin staining overlapped with clathrin, a coat protein involved in endocytosis. Immunoblot analysis of subcellular membrane fractions separated by differential centrifugation confirmed that huntingtin immunoreactivity in differentiated neurons markedly increased in membrane fractions enriched with clathrin and with huntingtin-interacting protein 1. Dopamine treatment altered the subcellular localization of huntingtin and increased its expression in clathrin-enriched membrane fractions. The dopamine-induced changes were blocked by the D1 antagonist SCH 23390 and were absent in a clonal cell line lacking D1 receptors. Results suggest that the transport of huntingtin and its co-expression in clathrin and huntingtin-interacting protein 1-enriched membranes is influenced by activation of adenylyl cyclase and stimulation of dopamine D1 receptors.

Animals↗
PubMed1999

A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration.

We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

Adaptation, Physiological↗
PubMed1999

Accurate determination of the number of CAG repeats in the Huntington disease gene using a sequence-specific internal DNA standard.

We have developed a sequence-specific internal DNA size standard for the accurate determination of the number of CAG repeats in the Huntington disease (HD) gene by cloning key fragments (between 15 and 64 CAG repeats) of the HD gene. These fragments, pooled to produce a sequence-specific DNA ladder, enabled us to observe the true number of CAG repeats directly, with no need for calculations. Comparison of the calculated numbers of CAG repeats in the HD gene using this sequence-specific DNA standard with a commercially available standard (GENESCAN-500 TAMRA) showed that the latter underestimated the number of CAG repeats by three when analyzed by capillary electrophoresis on the ABI 310 Genetic Analyzer (POP4 polymer). In contrast, the use of the same standard overestimated the number of CAG repeats by one when the samples were analyzed by denaturing polyacrylamide electrophoresis on ABI 377 DNA Sequencer (6% denaturing polyacrylamide gel). This suggests that our sequence-specific standard provides greater accuracy for the determination of the true number of CAG repeats in the HD gene than commercially available standards. The sequence-specific standard can be radioactively labeled and successfully replace conventional DNA size standards when analyzing polymerase chain reaction (PCR)-amplified HD alleles by denaturing polyacrylamide electrophoresis.

Alleles↗
PubMed1999

A common truncation variant of lipoprotein lipase (Ser447X) confers protection against coronary heart disease: the Framingham Offspring Study.

Genetic variation at the lipoprotein lipase (LPL) locus has been shown to influence plasma lipids and to modulate risk of coronary heart disease (CHD). Recently, we found that the most frequent variant at this locus, involving a C-terminal truncation of two amino acids (Ser447X), was associated with both higher LPL activity and high density lipoprotein cholesterol (HDL-C) in patients with CHD. However, the impact of this S447X variant on lipids and CHD in the general population was hitherto unknown. We, therefore, analyzed a total of 1114 men and 1144 women randomly ascertained from the Framingham Offspring Study (FOS) for the presence of this LPL variant. Carrier frequency of the S447X allele was 17%, and in men carrier status was associated with higher total cholesterol (delta = 6.2 mg/dl, p = 0.03). higher HDL-C (delta = 2.3 mg/dl, p = 0.01), and lower triglyceride (TG) levels (delta = -19.4 mg/dl, p = 0.02). Moreover, in men, the S447X allele conferred significant protection against CHD (odds ratio: 0.43; p = 0.04). These effects on lipids and CHD were not seen in women. Our study represents the first report on the impact of this mutation on CHD in men from the general population, and we conclude, therefore, that the S447X variant may confer significant protection against high TG levels, low HDL-C, and premature CHD in these subjects.

Adult↗