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M Farrer

Publications and source records attributed to M Farrer.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genetic analysis of synphilin-1 in familial Parkinson's disease.

alpha-Synuclein is present in Lewy bodies of patients with both sporadic and familial Parkinson's disease. However, pathogenic mutations Ala30Pro and Ala53Thr in alpha-synuclein are rare causes of disease. Synphilin-1 has been demonstrated to associate with alpha-synuclein and promote the formation of cytosolic inclusions in vitro. Two-point genetic linkage analysis of a dinucleotide repeat within the synphilin-1 gene initially implicated this locus as a cause of Parkinson's disease in three of nine families. However, subsequent haplotype, sequencing, and association analyses in these three families and an independent case-control series suggest that variability within the locus does not confer susceptibility to Parkinson's disease.

Aged↗
PubMed2001

Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter.

alpha-Synuclein has been identified as a major component of Lewy body inclusions, which are one of the pathologic hallmarks of idiopathic Parkinson's disease. Mutations in alpha-synuclein have been found to be responsible for rare familial cases of Parkinsonism. To test whether overexpression of human alpha-synuclein leads to inclusion formation and neuronal loss of dopaminergic cells in the substantia nigra, we made transgenic mice in which the expression of wild-type or mutant (A30P and A53T) human alpha-synuclein protein was driven by the promoter from the tyrosine hydroxylase gene. Even though high levels of human alpha-synuclein accumulated in dopaminergic cell bodies, Lewy-type-positive inclusions did not develop in the nigrostriatal system. In addition, the number of nigral neurons and the levels of striatal dopamine were unchanged relative to non-transgenic littermates, in mice up to one year of age. These findings suggest that overexpression of alpha-synuclein within nigrostriatal dopaminergic neurons is not in itself sufficient to cause aggregation into Lewy body-like inclusions, nor does it trigger overt neurodegenerative changes.

Animals↗
PubMed2001

Refinement of the PARK3 locus on chromosome 2p13 and the analysis of 14 candidate genes.

Parkinson's disease (PD) is a common neurodegenerative disorder with clinical features of bradykinesia, rigidity, resting tremor and postural instability resulting from the deficiency of dopamine in the nigrostriatal system. Previously we mapped a susceptibility gene for an autosomal dominant form of PD to a 10.6 cM region of chromosome 2p (PARK3; OMIM 602404). A common haplotype shared by two North American kindreds (Families B and C) genealogically traced to Southern Denmark and Northern Germany suggested a founder effect. Here we report progress in the refinement of the PARK3 locus and sequence analysis of candidate genes within the region. Members of families B and C were genotyped using polymorphic markers, reducing the minimum common haplotype to eight markers spanning a physical distance of 2.5 Mb. Analysis of 14 genes within the region did not reveal any potentially pathogenic mutations segregating with the disease, implying that none of these genes are likely candidates for PARK3.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Identification and characterization of the human parkin gene promoter.

Compound mutations and homozygous loss of function of the parkin gene causes juvenile and early onset, autosomal recessive parkinsonism. Pathologically, the disease is associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, usually without Lewy body pathology. Hemizygous families have been described that may harbor mutations outside of the open reading frame. The parkin gene promoter has yet to be characterized, and therein, mutations in hemizygous families may plausibly be identified. To identify the promoter of the parkin gene, the transcription start site was defined by a combination of primer extension and 5' RACE. Five kilobases of DNA 5' to the parkin start codon were directly sequenced from a BAC containing parkin exon 1 and evaluated for promoter motifs. The parkin promoter lacks TATA or CAAT boxes and appears to share homology to the alpha-synuclein promoter. Deletion constructs demonstrated core promoter activity and tissue specific enhancing regions in HEK-293T and SH-SY5Y cells.

5' Untranslated Regions↗
PubMed2001

Impact of first myocardial infarction on self-perceived health status.

Despite recent advances in the acute management of myocardial infarction (MI), few studies have evaluated self-perceived quality of life in the longer term after MI. We mailed a questionnaire incorporating the short form 12 (SF-12) and seeking information on symptoms, drug therapy, recent investigations and employment status, to 149 patients who had a first MI 2 years previously. The response rate was 82%. Mean physical and mental summary scores were significantly lower in patients than "normative" controls (physical summary score: 37.0+/-11.5 vs. 50.9+/-9.4; p<0.001 and mental summary score: 46.2+/-12.8 vs. 52.1+/-8.7; p<0.001, respectively). Physical and mental summary scores were closely associated with continuing chest pain at 2 years, level of limitation on daily activities and employment status. We found the SF-12 to be a useful tool for monitoring health status and believe it could be used to evaluate the impact of interventions on quality of life after acute MI. Self-perceived health status 2 years after a first MI remains poor despite advances in management.

Activities of Daily Living↗
PubMed2001

Left ventricular remodelling and brain natriuretic peptide after first myocardial infarction.

OBJECTIVE: To investigate the relation between brain natriuretic peptide (BNP) concentrations and left ventricular remodelling characteristics after acute myocardial infarction. DESIGN: Consecutive sample prospective cohort study. SETTING: District general hospital coronary care unit in the north of England. PATIENTS: 133 initial survivors of a first myocardial infarction who received thrombolytic treatment. INTERVENTIONS: Patients had transthoracic echocardiography and BNP concentrations measured at three to seven days (early) and two months (late). MAIN OUTCOME MEASURES: Wall motion index </= 1.2, end systolic left ventricular volume index and mortality at one year. RESULTS: Patients with an early wall motion index of </= 1.2 had higher early and late BNP concentrations (early BNP mean (SEM) 629 (76.2) pg/ml v 334 (20.8) pg/ml, p = 0.001 and late BNP 584 (79.5) pg/ml v 343 (25.0) pg/ml, p = 0.001). Patients with an increase in end systolic left ventricular volume index of > 10% also had higher early and late BNP concentrations (early BNP p = 0.034 and late BNP p = 0.001). Early BNP was significantly associated with one year mortality (p = 0.003). CONCLUSIONS: Higher BNP concentrations early after first myocardial infarction are associated with adverse left ventricular remodelling characteristics. This may help explain why BNP is such a strong predictor of outcome after myocardial infarction.

Cohort Studies↗
PubMed2000

Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.

OBJECTIVE: To describe the clinical and molecular genetic analysis of a large family of northern Chinese descent with a mutation at the SCA2 locus causing carbidopa-levodopa-responsive parkinsonism. BACKGROUND: Most causes of parkinsonism remain unknown. However, molecular genetic analysis of families with parkinsonism has recently identified five distinct loci and pathogenic mutations in four of those. Additionally, some of the spinocerebellar ataxia syndromes (SCA), particularly Machado-Joseph syndrome (SCA3), are known to cause parkinsonism. Spinocerebellar ataxia type 2 (SCA2) has not previously been described as causing a typical dopamine-responsive asymmetric PD phenotype. METHODS: A large family was evaluated clinically and molecularly for apparent autosomal dominant parkinsonism. RESULTS: The phenotype includes presentation consistent with typical dopamine-responsive parkinsonism. Other presentations in this family include a parkinsonism/ataxia phenotype, which is classic for SCA2 and parkinsonism, resembling progressive supranuclear palsy. CONCLUSIONS: Patients presenting with a family history of parkinsonism, including familial progressive supranuclear palsy and PD, should be tested for the spinocerebellar ataxia type 2 expansion.

Adult↗
PubMed2000

Linkage exclusion in French families with probable Parkinson' s disease.

We analyzed the segregation of genetic markers spanning chromosomal regions 2p13, 4p14-15, 4q21-23, 6q25-27, and 17q21 in nine French families affected by autosomal-dominant probable Parkinson's disease. These regions have been linked or associated with familial Parkinson's disease. Multipoint linkage and haplotype analyses excluded 2p13 and 4p14-15 loci in five of nine families. For three families, which were equivocal for two-point linkage at D4S405, the ubiquitin carboxy-terminal hydrolase gene (UCH-L1) was sequenced. In one family, a novel UCH-L1 M124L mutation that did not segregate with early-onset disease was identified. This suggests that rare variants in this gene may not be pathogenic. In seven of nine families, it could be inferred that affected individuals did not share 4q21-23 (alpha-synuclein) haplotypes. All families were unequivocally excluded by haplotype analysis from the parkin locus on 6q25-27. Finally, the 17q21 region was excluded in four of nine families, and no mutation in the tau gene was identified in the five remaining families. Findings from this study confirm genetic heterogeneity within familial parkinsonism.

Adult↗
PubMed2000

Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p.

The identification of the alpha-synuclein gene on chromosome 4q as a locus for familial Lewy-body parkinsonism and of alpha-synuclein as a component of Lewy bodies has heralded a new era in the study of Parkinson's disease. We have identified a large family with Lewy body parkinsonism linked to a novel locus on chromosome 4p15 that does not have a mutation in the alpha-synuclein gene. Here we report the clinical and neuropathological findings in an individual from this family and describe unusual high molecular weight alpha-synuclein-immunoreactive proteins in brain homogenates from brain regions with the most marked neuropathology. Distinctive histopathology was revealed with alpha-synuclein immunostaining, including pleomorphic Lewy bodies, synuclein-positive glial inclusions and widespread, severe neuritic dystrophy. We also discuss the relationship of this familial disorder to a Lewy body disease clinical spectrum, ranging from Parkinson's disease to dementia with psychosis.

Brain↗
PubMed2000

Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein.

Linkage of alpha-synuclein (alpha-SN) mutations to familial Parkinson's disease (PD) and presence of alpha-SN as a major constituent of Lewy body in both sporadic and familial PD implicate alpha-SN abnormality in PD pathogenesis. Here we demonstrate that overexpression of wild-type or mutant alpha-SN does not cause any deleterious effect on the growth or continued propagation of transfected human cells, but overproduction of mutant alpha-SN heightens their sensitivity to menadione-induced oxidative injury. Such enhanced vulnerability is more pronounced in neuronal transfectants than in their nonneuronal counterparts and is associated with increased production of reactive oxygen species. The data suggest that mutated alpha-SN, especially with an alanine-to-proline substitution at residue 30, sensitizes neuronal cells to oxidative damage.

Cell Line↗
PubMed1999

alpha-Synuclein shares physical and functional homology with 14-3-3 proteins.

alpha-Synuclein has been implicated in the pathophysiology of many neurodegenerative diseases, including Parkinson's disease (PD) and Alzheimer's disease. Mutations in alpha-synuclein cause some cases of familial PD (Polymeropoulos et al., 1997; Kruger et al., 1998). In addition, many neurodegenerative diseases show accumulation of alpha-synuclein in dystrophic neurites and in Lewy bodies (Spillantini et al., 1998). Here, we show that alpha-synuclein shares physical and functional homology with 14-3-3 proteins, which are a family of ubiquitous cytoplasmic chaperones. Regions of alpha-synuclein and 14-3-3 proteins share over 40% homology. In addition, alpha-synuclein binds to 14-3-3 proteins, as well as some proteins known to associate with 14-3-3, including protein kinase C, BAD, and extracellular regulated kinase, but not Raf-1. We also show that overexpression of alpha-synuclein inhibits protein kinase C activity. The association of alpha-synuclein with BAD and inhibition of protein kinase C suggests that increased expression of alpha-synuclein could be harmful. Consistent with this hypothesis, we observed that overexpression of wild-type alpha-synuclein is toxic, and overexpression of alpha-synuclein containing the A53T or A30P mutations exhibits even greater toxicity. The activity and binding profile of alpha-synuclein suggests that it might act as a protein chaperone and that accumulation of alpha-synuclein could contribute to cell death in neurodegenerative diseases.

14-3-3 Proteins↗
PubMed1999

No pathogenic mutations in the beta-synuclein gene in Parkinson's disease.

We present 11 families consistent with autosomal dominant inheritance of probable Parkinson's disease (PD). Although excluded as a cause of disease in these kindreds, mutations in the alpha-synuclein gene have been implicated in familial PD. The beta-synuclein gene is highly homologous, expressed in the nervous system and thus is a good candidate gene for PD. Multipoint linkage analysis was either equivocal or excluded 5q35 haplotype sharing among affected family members. Sequencing the translated exons of the beta-synuclein gene failed to identify any pathogenic mutation.

Adult↗
PubMed1999

Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease.

A coding substitution (I93M) in the ubiquitin carboxy-terminal L1 (UCH-L1) gene has recently been identified in a German family with Parkinson's disease. We have sequenced the entire coding region of the gene in 11 families who have a pattern of disease consistent with autosomal dominant inheritance. We found a polymorphism (S18Y) in exon 3, two polymorphisms in the 5' non-coding region, upstream of the transcription start, and an insertion/deletion polymorphism in intron 4. The S18Y allele is present on approximately 20% of chromosomes in a Caucasian population. These changes are, therefore, unlikely to be pathogenic. We conclude that the I93M variant must either be a rare cause of disease or a harmless substitution whose occurrence in the family reflects a chance co-occurrence.

Adult↗
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

Widespread alterations of alpha-synuclein in multiple system atrophy.

Glial cytoplasmic inclusions (GCI) are the hallmark of multiple system atrophy (MSA), a rare movement disorder frequently associated with autonomic dysfunction. In this study of 21 cases of MSA, GCI were consistently immunoreactive for alpha-synuclein and double-immunostained for ubiquitin and oligodendroglial markers, but not glial fibrillary acidic protein. No statistically significant difference was found in the density of GCI in various brain regions in the two forms of MSA, striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA). Postmortem brain samples from 9 cases of MSA were fractionated according to solubility in buffer, Triton-X 100, sodium dodecyl sulfate (SDS), and formic acid, and alpha-synuclein immunoreactivity was measured in Western blots. Total alpha-synuclein immunoreactivity was increased in MSA compared to controls, with no statistically significant difference between SND and OPCA. Most of the increase was due to alpha-synuclein in SDS fractions. In controls this fraction had little or no immunoreactivity. In 7 cases and 4 controls correlations were investigated between quantitative neuropathology and biochemical properties of alpha-synuclein. Surprisingly, the amount of SDS-soluble alpha-synuclein correlated poorly with the number of GCI in adjacent sections. Furthermore, areas with few or no GCI unexpectedly had abundant SDS-soluble alpha-synuclein. These findings provide evidence that modifications of alpha-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies.

Aged↗
PubMed1999

Acute effects of nebulised epoprostenol in pulmonary hypertension due to systemic sclerosis.

Pulmonary hypertension often has a lethal outcome in systemic sclerosis and the treatment is challenging. Epoprostenol is a potent pulmonary vasodilator and its efficacy has been demonstrated when delivered by the intravenous and aerosolized routes. We report the haemodynamic and functional benefits of epoprostenol administered by inhalation to a spontaneously breathing patient with partially reversible pulmonary hypertension due to systemic sclerosis. Aerosolized epoprostenol, equivalent to the maximum tolerated intravenous dose (31.2 micrograms), produced a 58% fall in pulmonary vascular resistance, increased the cardiac output by 42% and improved functional performance by one MET (3.5 ml kg-1 min-1 of oxygen uptake) without any significant side-effects. Selective distribution of epoprostenol by the inhaled route may offer a new strategy for treatment of pulmonary hypertension.

Administration, Inhalation↗
PubMed1999

A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor.

We investigated a large family with levodopa-responsive, Lewy body parkinsonism in which the disease segregates as an apparent autosomal dominant trait. After performing a genome screen, we identified a chromosome 4p haplotype that segregates with the disease. However, this haplotype also occurs in individuals in the pedigree who do not have clinical Lewy body parkinsonism but rather suffer from postural tremor, consistent with essential tremor. These data demonstrate a new locus for Lewy body parkinsonism and suggest that in some circumstances postural tremor can be an alternative phenotype of the samepathogenic mutation as Lewy body parkinsonism.

Chromosome Mapping↗