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Biomedical subjects

John Hardy

Publications and source records attributed to John Hardy.

At least 91 records · Page 5Linked to original sources
PubMed2004

No evidence for tau duplications in frontal temporal dementia families showing genetic linkage to the tau locus in which tau mutations have not been found.

Given the remarkable similarities between the genetics of tau diseases and the genetics of alpha-synuclein diseases, and given the fact that we have recently found a triplication of the alpha-synuclein locus in a family in which we had shown linkage to the alpha-synuclein locus, we determined to test whether some of the several families with autosomal dominant frontal temporal dementia which show genetic linkage to the tau locus but in which tau mutations have not been found could be caused by similar structural mutations. We did not find any such mutations.

Chromosome Mapping↗
PubMed2004

The structure of the tau haplotype in controls and in progressive supranuclear palsy.

The group of neurodegenerative diseases collectively known as tauopathies are characterized by hallmark lesions consisting of fibrillar aggregates of the microtubule-associated protein, tau (MAPT). Mutations of the tau gene (MAPT) are the cause of frontotemporal dementia with parkinsonism linked to chromosome 17, giving tau a central role in the pathogenic process. The chromosomal region containing MAPT has been shown to evolve into two major haplotypes, H1 and H2, which are defined by linkage disequilibrium (LD) between several polymorphisms over the entire MAPT gene. Studies to date suggest a complete absence of recombination between these two haplotypes. The more common haplotype H1 is over-represented in patients with progressive supranuclear palsy (PSP) and corticobasal degeneration. Using single nucleotide polymorphisms, we mapped LD in the regions flanking MAPT and have established the maximum extent of the haplotype block on chromosome 17q21.31 as a region covering approximately 2 Mb. This gene-rich region extends centromerically beyond the corticotrophin releasing hormone receptor 1 gene (CRHR1) to a region of approximately 400 kb, where there is a complete loss of LD. The telomeric end is defined by an approximately 150 kb region just beyond the WNT3 gene. We show that the entire, fully extended H1 haplotype is associated with PSP, which implicates several other genes in addition to MAPT, as candidate pathogenic loci.

Haplotypes↗
PubMed2004

An association study of the cholesteryl ester transfer protein TaqI B polymorphism with late onset Alzheimer's disease.

Cholesteryl ester transfer protein (CETP) is reportedly able to affect the amount of cholesterol available for deposition and/or removal from peripheral tissues, in its capacity to mediate the transfer of cholesterol from high density lipoprotein (HDL) to very low density lipoprotein, in exchange for triacylglycerols from the latter. The TaqI B polymorphism of the human CETP gene has been associated with decreased CETP mass and an increase in HDL-cholesterol. While many studies have addressed the atherogenic or anti-atherogenic potential of this polymorphism, little is known about its effect on neurodegeneration, despite the fact that CETP is expressed in the brain and the disturbance of cholesterol homeostasis appears to be an important factor in the pathogenesis of Alzheimer's disease (AD). In this report, we have compared the distribution of the TaqI B polymorphism in an independent population of 102 clinically diagnosed late onset AD patients and a spousal control group of 97 individuals. We have also examined the possible interaction between this polymorphism and two other polymorphisms suspected of affecting cholesterol flux, namely apolipoprotein E APOE epsilon4, and lipoprotein lipase LPLS447X. No statistically significant differences have emerged with respect to either genotype or allele frequencies between the AD and control populations. CETP TaqI B did not interact significantly with either APOE epsilon4 or LPLS447X, in this study.

Aged↗
PubMed2004

The law of mass action applied to neurodegenerative disease: a hypothesis concerning the etiology and pathogenesis of complex diseases.

Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creuzfeldt-Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia, and alpha-synuclein mutations cause autosomal dominant Parkinson's disease. In all these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and in these cases the whole protein is deposited. In Alzheimer's disease, mutations in APP or presenilin 1 or 2 cause autosomal dominant disease and these are the substrate and proteases, respectively, which are responsible for the production of the deposited peptide, Abeta. Thus, in all cases, the mutations lead to the disease by a mechanism that involves the deposition process. We briefly review this remarkably predictable biology, but also point out that it seems sporadic forms of all these diseases are predisposed to by genetic variability at the same loci, strongly suggesting that the quantity of the normal protein produced influences risk for the sporadic forms of the disease. The evidence for this assertion is strongest in Parkinson's disease (PD), where genetic variability in alpha-synuclein expression affects risk of developing disease, although the oldest evidence for the notion that increased expression of normal sequence protein can lead to disease comes from the observation of Alzheimer's disease in trisomy 21 cases. From these observations, we make predictions concerning the etiology and pathogenesis of neurodegenerative diseases in general.

Haplotypes↗
PubMed2004

Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation.

The +16 exon 10 splice mutation of the tau gene (microtubule-associated protein tau, MAPT) has been reported in numerous families with frontotemporal dementia (FTD). To date, the majority of these families are from England and Wales in the UK, although families with this mutation have been reported from Australia and the USA. Our own analysis has identified eight families with the +16 MAPT splice mutation from around the Manchester and North Wales areas of the UK. Given the proximity of the UK families to one another it is likely that they are related and represent a single extended pedigree. In order to investigate this possibility, and the possibility that the families with this mutation from London, the USA, and Australia are related, we genotyped 11 microsatellite markers around the tau locus. In most cases (20/25, 80%), a common haplotype, approximately 3 cM in size, was identified. In the remaining cases, this haplotype appears to have been varyingly reduced in size by recombination. We demonstrate that the +16 mutation is on the H1 tau haplotype and that H1 specific polymorphisms are also shared by these families. These data provide evidence that the MAPT +16 splice mutation cases from around the world analyzed in this study are indeed related and represent a single pedigree that probably originated in the North Wales area of the UK. Furthermore, this single large pedigree may be of use in the identification of disease modifying loci in FTD.

Australia↗
PubMed2004

CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation.

Molecular chaperones, ubiquitin ligases and proteasome impairment have been implicated in several neurodegenerative diseases, including Alzheimer's and Parkinson's disease, which are characterized by accumulation of abnormal protein aggregates (e.g. tau and alpha-synuclein respectively). Here we report that CHIP, an ubiquitin ligase that interacts directly with Hsp70/90, induces ubiquitination of the microtubule associated protein, tau. CHIP also increases tau aggregation. Consistent with this observation, diverse of tau lesions in human postmortem tissue were found to be immunopositive for CHIP. Conversely, induction of Hsp70 through treatment with either geldanamycin or heat shock factor 1 leads to a decrease in tau steady-state levels and a selective reduction in detergent insoluble tau. Furthermore, 30-month-old mice overexpressing inducible Hsp70 show a significant reduction in tau levels. Together these data demonstrate that the Hsp70/CHIP chaperone system plays an important role in the regulation of tau turnover and the selective elimination of abnormal tau species. Hsp70/CHIP may therefore play an important role in the pathogenesis of tauopathies and also represents a potential therapeutic target.

Animals↗
PubMed2004

Association between cardiac denervation and parkinsonism caused by alpha-synuclein gene triplication.

Parkinson's disease patients frequently have symptoms and signs of autonomic nervous dysfunction that are the source of considerable disability. Recent studies have revealed that most patients with Parkinson's disease, and all with Parkinson's disease-associated orthostatic hypotension, have a loss of cardiac sympathetic innervation. Familial Parkinson's disease, caused by mutation of the gene encoding alpha-synuclein, also features orthostatic hypotension, sympathetic neurocirculatory failure and cardiac sympathetic denervation. We have recently described a whole-gene triplication of alpha-synuclein causing Lewy body parkinsonism in a large, well characterized family called the 'Iowa kindred'. Here we report the results of cardiac PET scanning using the sympathoneural imaging agent, 6-[18F]fluorodopamine in affected and unaffected members of this kindred. Four family members were studied, two with parkinsonism, one clinically normal and one with benign essential tremor alone. Both affected members had obvious loss of cardiac sympathetic innervation; the unaffected member had normal innervation, as did the member with isolated essential tremor. The results indicate that, in this family, where disease is caused by overexpression of normal alpha-synuclein, cardiac sympathetic denervation cosegregates with parkinsonism. Post-mortem studies have demonstrated synuclein-positive Lewy body formation in the brains of individuals with parkinsonism who were also in the family described here and who also carry this triplication. These results indicate that both parkinsonism and cardiac sympathetic denervation can result from an excess of normal synuclein.

Aged↗
PubMed2004

alpha-Synuclein selectively increases manganese-induced viability loss in SK-N-MC neuroblastoma cells expressing the human dopamine transporter.

The established or potentially toxic agents implicated in the nigral cell death in Parkinson's disease, dopamine, 1-methyl-4-phenylpyridinium (MPP(+)), iron, and manganese, were examined as to their effects on the viability of cells overexpressing alpha-synuclein. SK-N-MC neuroblastoma cells stably expressing the human dopamine transporter were transfected with human alpha-synuclein and cell clones with and without alpha-synuclein immunoreactivity were obtained. Cells were exposed for 24-72 h to 1-10 microM dopamine, 0.1-3 microM MPP(+), 0.1-1 mM FeCl(2) or 30-300 microM MnCl(2) added to the culture medium. There was no difference between cells expressing alpha-synuclein and control cells after exposure to dopamine, MPP(+) or FeCl(2). However, MnCl(2) resulted in a significantly stronger decreased viability of cells overexpressing alpha-synuclein after 72 h. These findings suggest that manganese may co-operate with alpha-synuclein in triggering neuronal cell death such as seen in manganese parkinsonism. The relevance of our observations for the pathoetiology of Parkinson's disease proper remains to be determined.

1-Methyl-4-phenylpyridinium↗
PubMed2004

Variation in the urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD.

Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.

Aged↗
PubMed2004

Genome-wide analysis of the parkinsonism-dementia complex of Guam.

BACKGROUND: Parkinsonism-dementia complex (PDC) is a neurofibrillary tangle degeneration involving the deposition of Alzheimer-type tau, predominantly in the mesial temporal cortex, brainstem, and basal ganglia. It occurs in focal geographic isolates, including Guam and the Kii peninsula of Japan. The familial clustering of the disease has suggested that a genetic factor could be important in its etiology. OBJECTIVE: To determine whether a genetic locus could be identified, linked, or associated with PDC. DESIGN AND PATIENTS: We performed a genome-wide association study of 22 Guamanian PDC and 19 control subjects using 834 microsatellite markers with an approximate genome-wide marker density of 4.4 centimorgans. RESULTS: Two-point association analysis identified 17 markers (P<.015). Each of these markers then underwent conventional linkage analysis in 5 families with PDC. One marker, D20S103, generated a logarithm of odds score of greater than 1.5. Multipoint association analysis also highlighted 2 other areas on chromosome 14q (adjacent to D14S592, 59.2 megabases [M]) and chromosome 20 (adjacent to D20S470, 17.4 M) with multipoint association logarithm of the odds scores of greater than 2. The areas around D20S103, D14S592, and D20S470 were further analyzed by association using additional microsatellite markers and by conventional linkage analysis. This did not provide further evidence for the role of these areas in PDC. CONCLUSIONS: This study has not identified a single gene locus for PDC, confirming the impression of a geographic disease isolate with a complex genetic, a genetic/environmental etiology, or a purely environmental etiology.

Aged↗
PubMed2004

Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.

BACKGROUND: Mutations in the PTEN-induced kinase (PINK1) gene located within the PARK6 locus on chromosome 1p35-p36 have recently been identified in patients with recessive early-onset Parkinson disease. OBJECTIVE: To assess the prevalence of PINK1 mutations within a series of early- and late-onset Parkinson disease patients living in North America. DESIGN: All coding exons of the PINK1 gene were sequenced in a series of 289 Parkinson disease patients and 80 neurologically normal control subjects; the mutation frequencies were evaluated in additional controls (100 white and 50 Filipino subjects). RESULTS: We identified 27 variants, including the first reported compound heterozygous mutation (Glu240Lys and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-onset Parkinson disease patients. CONCLUSION: Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease.

Adolescent↗
PubMed2004

Parkinson's disease in Ireland: clinical presentation and genetic heterogeneity in patients with parkin mutations.

Early-onset autosomal recessive parkinsonism is associated with parkin gene mutations. Different parkin mutations occur in many ethnic backgrounds; however, the phenotype may vary. We studied 102 young-onset (age at onset <60 years) Parkinson's disease (PD) patients. From 102 patients, 40 with early-onset PD (<45 years at symptomatic onset) were selected for clinical assessment and parkin gene molecular analysis for duplications/deletions and point mutations. We identified parkin mutations in 7 of 40 early-onset patients; including novel compound heterozygotes and potential splice site changes. The mean age at onset in the 7 parkin mutation-positive patients was 33 +/- 9 years (age range, 18-42 years), marginally lower than that of the 33 parkin-negative early-onset patients, 38 +/- 7 years (age range, 17-45 years). A family history of PD was present in 4 of 7 patients with parkin mutations, compared with 6 of 33 early-onset parkin-negative patients. Overall, parkin mutations were found in 4 of 10 patients with a positive family history and 3 of 30 patients without a family history of PD. Patients with parkin mutations had more dystonia, dyskinesia, and sleep benefit compared with parkin-negative patients. We subsequently identified a single point mutation among the 62 young-onset (age at onset 45 to <60 years). Mutations in the parkin gene may account for approximately 17% of early-onset (age at onset <45 years) parkinsonism in Ireland, in agreement with previous European studies.

Adolescent↗
PubMed2004

A consanguineous Turkish family with early-onset Parkinson's disease and an exon 4 parkin deletion.

The importance of parkin in early-onset Parkinson's disease in Japan, Europe, and the United States is well established. The contribution of this gene to the risk of Parkinson's disease in other populations is less well known. To explore the importance of parkin in those of Turkish ancestry, we studied familial cases from that country, and identified a consanguineous family with early-onset Parkinson's disease due to a homozygous mutation in parkin.

Consanguinity↗
PubMed2004

Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.

Antiparkinson Agents↗
PubMed2004

Analysis of an early-onset Parkinson's disease cohort for DJ-1 mutations.

The frequency and relative contribution of DJ-1 mutations in early-onset Parkinson's disease (EOPD) is currently unknown. We analyzed a cohort of 89 EOPD patients (mean age at onset of PD +/- SD, 41.5 +/- 7.2 years), ascertained independent of family history, who participated in a study of the genetic epidemiology of PD. This study includes sequence analysis of the DJ-1 gene in addition to assaying the 14,082-bp deletion spanning exons 1 to 5, previously identified in a Dutch kindred, in 89 EOPD cases. A heterozygous missense mutation in exon 5 (A104T) was identified in an EOPD case of Asian ethnicity; this sequence variant was absent in 308 control chromosomes. We identified additional sequence variation in the DJ-1 gene, including a polymorphism in the coding region in exon 5 (R98Q), three polymorphisms in the 5' untranslated region (exon 1A/1B), and two polymorphisms in intronic regions (IVS1 and IVS5). Mutations in the DJ-1 gene are rare in EOPD in both sporadic and familial cases.

Adult↗
PubMed2004

Analysis of familial and sporadic restless legs syndrome in age of onset, gender, and severity features.

Restless Legs Syndrome is characterized by the irresistible, often indescribable unpleasant urge to move the limbs while resting. It has an estimated prevalence of approximately 29.3 % in US private practice. Restless Legs Syndrome often has a familial component; whether the familial and non-familial forms differ in terms of clinical features has previously been investigated, with the only significant factor emerging as younger age at onset in familial cases. Our study further explores a possible underlying difference between familial and sporadic forms of RLS by comparing familial RLS with sporadic RLS in terms of demographic and clinical features including subject gender, age of onset, and severity measures based an the IRLSSG severity scale. Both gender and family history are significant predictors of onset age in an overall model and also significant when analyzed independently. Participants who reported more severe RLS symptoms were significantly younger in age and progressed more rapidly. Two variables from the IRLSSG severity scale were significantly associated with age of onset when tested independently: discomfort and the urge to move the limb for relief. Our analysis supports the prevailing hypothesis that RLS is divided into earlier onset disease with a clear genetic component and later onset disease with unclear etiology, and that one or more endophenotypes might exist within the disorder which could further characterize these subjects for future genetic studies.

Age of Onset↗