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J Collinge

Publications and source records attributed to J Collinge.

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

Prion diseases of humans and animals: their causes and molecular basis.

Prion diseases are transmissible neurodegenerative conditions that include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals. Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein, prion protein. Prion propagation involves recruitment of host cellular prion protein, composed primarily of alpha-helical structure, into a disease specific isoform rich in beta-sheet structure. The existence of multiple prion strains has been difficult to explain in terms of a protein-only infections agent, but recent studies suggest that strain specific phenotypes can be encoded by different prion protein conformations and glycosylation patterns. The ability of a protein to encode phenotypic information has important biological implications. The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, and the barriers limiting intermammalian transmission. It is unclear if a large epidemic of variant CJD will occur in the years ahead.

Animals↗
PubMed2001

Report on the first polish case of the Gerstmann-Sträussler-Scheinker syndrome.

In the course of epidemiological studies on Creutzfeldt-Jakob Disease in Poland, the authors found a male patient aged 54 years with dementia rapidly progressing for a year and ataxia of the extremities. EEG tracings were abnormal but without features typical of CJD. About six months after hospitalisation the patient died. Neuropathological examination of his brain demonstrated spongiform lesions of medium intensity present mainly in the cortex of frontal and occipital lobes, with slight proliferation of astroglia. In the cerebellar cortex numerous deposits of PAS-positive substance amorphous or in the shape of kuru plaques were disclosed. A smaller number of these plaques were found in the cortex of occipital and temporal lobes, and in the putamen. All deposits stained strongly with monoclonal 3F4 antibody to human prion protein (PrP). Genetic studies disclosed in the 20th chromosome, in the PrP gene, mutation at codon 102 (P102L). Codon 129 was homozygous for methionine (M129M). It was established, moreover, that patient's father had at the same age a similar disease and died after one year and patient's sister died after a six-year-long neurological disease diagnosed as multiple sclerosis. On the basis of clinical, genetic and neuropathological findings the authors diagnosed the Gerstmann-Sträussler-Scheinker syndrome, a familial prion disease with autosomal dominant character. This is the first report on this syndrome in Poland.

Brain↗
PubMed2001

Transmission of scrapie by steel-surface-bound prions.

BACKGROUND: Prions are unusually resistant to conventional disinfection procedures. An electrode used intracerebrally on a Creutzfeldt-Jakob disease (CJD) patient transmitted the disease to two patients in succession and finally to a chimpanzee, despite attempted disinfection. Concerns that surgical instruments may transmit variant CJD have been raised by the finding of PrP(Sc), a surrogate marker for infectivity, in various tissues other than brain. MATERIALS AND METHODS: Stainless steel wire was exposed to scrapie-infected brain or brain homogenate, washed exhaustively and inserted into the brain of indicator mice to measure infectivity. RESULTS: A contact time of 5 min with scrapie-infected mouse brain suffices to render steel wire highly infectious and insertion of infectious wire into the brain of an indicator mouse for 30 min suffices to cause disease. Infectivity bound to wires persists far longer in the brain than when injected as homogenate, which can explain the extraordinary efficiency of wire-mediated infection. No detectable amounts of PrP could be eluted with NaOH, however the presence of PrP on infectious wires was demonstrated by chemiluminescence. Several recommended sterilisation procedures inactivated wire-bound mouse prions, but exposure to 10% formaldehyde was insufficient. CONCLUSIONS: Prions are readily and tightly bound to stainless steel surfaces and can transmit scrapie to recipient mice after short exposure times. This system mimics contaminated surgical instruments and will allow an assessment of sterilisation procedures.

Animals↗
PubMed2001

The molecular pathology of CJD: old and new variants.

The study of prion disease has become an area of intense interest since experimental evidence emerged for the transmission of phenotypic variation without the involvement of a nucleic acid component. Additional impetus has come from the widespread concern that exposure to bovine spongiform encephalopathy contaminated material poses a distinct and, conceivably, a severe threat to public health in the UK and other countries. The occurrence of new variant Creutzfeldt-Jakob disease has dramatically highlighted the need for a precise understanding of the molecular basis of prion propagation. The molecular basis of prion strain diversity, previously a major challenge to the "protein only" model, can now be reconciled with propagation of infectious protein topologies. The conformational change known to be central to prion propagation, from a predominantly alpha-helical fold to one predominantly comprising beta-structure, can now be reproduced in vitro, and the ability of beta-PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation. Concomitantly, advances in the fundamental biology of prion disease have done much to reinforce the protein only hypothesis of prion replication.

Animals↗
PubMed2000

Species-barrier-independent prion replication in apparently resistant species.

Transmission of prions between mammalian species is thought to be limited by a "species barrier," which depends on differences in the primary structure of prion proteins in the infecting inoculum and the host. Here we demonstrate that a strain of hamster prions thought to be nonpathogenic for conventional mice leads to prion replication to high levels in such mice but without causing clinical disease. Prions pathogenic in both mice and hamsters are produced. These results demonstrate the existence of subclinical forms of prion infection with important public health implications, both with respect to iatrogenic transmission from apparently healthy humans and dietary exposure to cattle and other species exposed to bovine spongiform encephalopathy prions. Current definitions of the species barrier, which have been based on clinical end-points, need to be fundamentally reassessed.

Animals↗
PubMed2000

Examination of the human prion protein-like gene doppel for genetic susceptibility to sporadic and variant Creutzfeldt-Jakob disease.

A novel human gene named Doppel (DPL) that has homology to the prion protein gene (PRNP) has recently been identified on chromosome 20p. By automated sequencing we have found a common (M174T, 48%) and an uncommon coding polymorphism. The polymorphic frequency of the M174T allele was examined in cases of variant and sporadic Creutzfeldt-Jakob Disease and compared with the frequency in the normal UK population. In sharp distinction to the M129V polymorphism of PRNP we have not found any evidence of disease association nor is there any association with age of onset, disease duration, or prion protein (PrP(Sc)) strain type.

Chromosomes, Human, Pair 20↗
PubMed2000

Prion disease--the propagation of infectious protein topologies.

Prion propagation is associated with accumulation of a conformational isomer of host encoded cellular prion protein, PrP(C). Solution structures of several mammalian PrPs have now been reported and they have stimulated a significant advance in our understanding of the folding dynamics of PrP. Studies on recombinant PrP have shown the polypeptide chain is able to adopt different topologies in different solvent conditions. Concomitantly, advances in the analysis of the abnormal isoform, PrP(Sc), have expanded our knowledge on the molecular basis of prion strains and have done much to reinforce the protein-only hypothesis of prion replication.

Animals↗
PubMed2000

Alzheimer's disease due to an intronic presenilin-1 (PSEN1 intron 4) mutation: A clinicopathological study.

We describe 21 affected individuals from a kindred with early-onset autosomal dominant familial Alzheimer's disease caused by an intronic presenilin-1 mutation (in intron 4). Mean age at onset of symptoms was 37.4 years [95% confidence interval (CI): 36.6-38.2 years], mean age at death was 44.7 years (95% CI: 43.1-46.3 years) and mean duration of illness was 7.3 years (95% CI: 5.9-8.7 years). Myoclonus and seizures were prominent features of this pedigree. In the four cases for whom neuropsychometric data were available, verbal memory impairment preceded visual memory deficits; naming was relatively preserved until late in the disease. One of these four cases underwent serial volumetric MRI scans demonstrating in vivo brain tissue loss of 3.9% (38.9 ml, annualized rate of atrophy: 1. 7%) over 22 months of follow-up. The four individuals who had necropsies demonstrated the neuropathological hallmarks of Alzheimer's disease. Apolipoprotein E (APOE) status was assessed in five individuals: the case with the youngest age at onset at 33 years of age was found to be homozygous epsilon4/epsilon4, > 1 SD below the mean age of onset for those of known APOE genotype (36.4 +/- 2.3 years, mean +/- SD), and > 2 SDs below the mean age of onset for the pedigree as a whole (37.4 +/- 1.7 years, mean +/- SD). APOE genotype may therefore modulate age at onset in this pedigree.

Adult↗
PubMed2000

Ostomy as a risk factor for posttraumatic infection in penetrating colonic injuries: univariate and multivariate analyses.

BACKGROUND: Primary repair for penetrating colonic injury is an acceptable practice in uncomplicated injuries, but it is still viewed with trepidation in high risk patients. METHODS: The records of 350 patients evaluated at an urban Level I trauma center for penetrating colonic injuries over an 8-year period (1989-1997) were reviewed. These included 33 stab and 317 gunshot wounds. Thirty-nine patients died within 48 hours. Of the remaining 311 patients, 78 (25%) developed 152 infections. These infections were classified as traumatic or nosocomial in nature. Traumatic infections (46%) included abdominal abscesses or peritonitis (28), wound infections (30), missile tract infections (8), and fistulas (4), whereas nosocomial infections (54%) included pneumonia (25), bacteremia (25), urinary tract infections (17), miscellaneous (8), empyema (4), and sinusitis (3). Significance for analyses was set at p < 0.05. RESULTS: Univariate analysis was performed to identify risk factors for the development of infections. The five most significant risk factors, using all infections as an outcome, were as follows: penetrating abdominal trauma index (PATI) greater than 30, presence of an ostomy, multiple transfusions, Injury Severity Score (ISS) of 16 or greater, and Revised Trauma Score less than 7.8. All were highly significant (p < 0.0001). Multivariate analysis with all infections as an outcome revealed that four of the five risk factors had independent effects, with the following significance: PATI greater than 30, ISS of 16 or greater, ostomy, and multiple transfusions. Multivariate analysis for traumatic infections revealed only two of the above to be independent risk factors: presence of an ostomy (p = 0.004) and a PATI greater than 30 (p = 0.039), both of which can be considered local factors. Conversely, multivariate analysis of nosocomial infections revealed independent risk for the two other factors, both of which can be considered systemic factors: multiple transfusions (p = 0.011) and ISS of 16 or greater (p = 0.026). CONCLUSION: Although most of the above factors are beyond the control of the trauma surgeon, the creation of an ostomy is a clinical decision. The creation of an ostomy in high-risk patients does not protect them from septic complications and, indeed, may independently contribute to local abdominal infections.

Adolescent↗
PubMed1999

Variant Creutzfeldt-Jakob disease.

It is clear that the prion strain causing bovine spongiform encephalopathy (BSE) in cattle has infected human beings, manifesting itself as a novel human prion disease, variant Creutzfeldt-Jakob disease (CjD). Studies of the incubation periods seen in previous epidemics of human prion disease and of the effect of transmission barriers limiting spread of these diseases between species, suggest that the early variant CJD cases may have been exposed during the preclinical phase of the BSE epidemic. It must therefore be considered that many cases may follow from later exposure in an epidemic that would be expected to evolve over decades. Since the number of people currently incubating this disease is unknown, there are concerns that prions might be transmitted iatrogenically via blood transfusion, tissue donation, and, since prions resist routine sterilisation, contamination of surgical instruments. Such risks remain unquantified. Although variant CJD can be diagnosed during life by tonsil biopsy, a prion-specific blood test is needed to assess and manage this potential threat to public health. The theoretical possibility that BSE prions might have transferred to other species and continue to present a risk to human health cannot be excluded at present.

Animals↗
PubMed1999

Multiple folding pathways for heterologously expressed human prion protein.

Human PrP (residues 91-231) expressed in Escherichia coli can adopt several conformations in solution depending on pH, redox conditions and denaturant concentration. Oxidised PrP at neutral pH, with the disulphide bond intact, is a soluble monomer which contains 47% alpha-helix and corresponds to PrPC. Denaturation studies show that this structure has a relatively small, solvent-excluded core and unfolds to an unstructured state in a single, co-operative transition with a DeltaG for folding of -5.6 kcal mol-1. The unfolding behaviour is sensitive to pH and at 4.0 or below the molecule unfolds via a stable folding intermediate. This equilibrium intermediate has a reduced helical content and aggregates over several hours. When the disulphide bond is reduced the protein adopts different conformations depending upon pH. At neutral pH or above, the reduced protein has an alpha-helical fold, which is identical to that observed for the oxidised protein. At pH 4 or below, the conformation rearranges to a fold that contains a high proportion of beta-sheet structure. In the reduced state the alpha- and beta-forms are slowly inter-convertible whereas when oxidised the protein can only adopt an alpha-conformation in free solution. The data we present here shows that the human prion protein can exist in multiple conformations some of which are known to be capable of forming fibrils. The precise conformation that human PrP adopts and the pathways for unfolding are dependent upon solvent conditions. The conditions we examined are within the range that a protein may encounter in sub-cellular compartments and may have implications for the mechanism of conversion of PrPC to PrPSc in vivo. Since the conversion of PrPC to PrPSc is accompanied by a switch in secondary structure from alpha to beta, this system provides a useful model for studying major structural rearrangements in the prion protein.

Circular Dichroism↗
PubMed1999

Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations.

Prion propagation involves the conversion of cellular prion protein (PrPC) into a disease-specific isomer, PrPSc, shifting from a predominantly alpha-helical to beta-sheet structure. Here, conditions were established in which recombinant human PrP could switch between the native alpha conformation, characteristic of PrPC, and a compact, highly soluble, monomeric form rich in beta structure. The soluble beta form (beta-PrP) exhibited partial resistance to proteinase K digestion, characteristic of PrPSc, and was a direct precursor of fibrillar structures closely similar to those isolated from diseased brains. The conversion of PrPC to beta-PrP in suitable cellular compartments, and its subsequent stabilization by intermolecular association, provide a molecular mechanism for prion propagation.

Circular Dichroism↗
PubMed1999

Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples.

BACKGROUND: Prion diseases are associated with the accumulation of an abnormal isoform of cellular prion protein (PrPSc), which is the principal constituent of prions. Prions replicate in lymphoreticular tissues before neuroinvasion, suggesting that lymphoreticular biopsy samples may allow early diagnosis by detection of PrPSc. Variant Creutzfeldt-Jakob disease (variant CJD) is difficult to distinguish from common psychiatric disorders in its early stages and definitive diagnosis has relied on neuropathology. We studied lymphoreticular tissues from a necropsy series and assessed tonsillar biopsy samples as a diagnostic investigation for human prion disease. METHODS: Lymphoreticular tissues (68 tonsils, 64 spleens, and 40 lymph nodes) were obtained at necropsy from patients affected by prion disease and from neurological and normal controls. Tonsil biopsy sampling was done on 20 patients with suspected prion disease. Tissues were analysed by western blot to detect and type PrPSc, by PrP immunohistochemistry, or both. FINDINGS: All lymphoreticular tissues obtained at necropsy from patients with neuropathologically confirmed variant CJD, but not from patients with other prion diseases or controls, were positive for PrPSc. In addition, PrPSc typing revealed a consistent pattern (designated type 4t) different from that seen in variant CJD brain (type 4) or in brain from other CJD subtypes (types 1-3). Tonsil biopsy tissue was positive in all eight patients with an adequate biopsy sample and whose subsequent course has confirmed, or is highly consistent with, a diagnosis of variant CJD and negative in all patients subsequently confirmed to have other diagnoses. INTERPRETATION: We found that if, in the appropriate clinical context, a tonsil biopsy sample was positive for PrPSc, variant CJD could be diagnosed, which obviates the need for a brain biopsy sample to be taken. Our results also show that variant CJD has a different pathogenesis to sporadic CJD.

Adolescent↗
PubMed1999

Pathogenic presenilin 1 mutations (P436S & I143F) in early-onset Alzheimer's disease in the UK. Mutations in brief no. 223. Online.

Familial Alzheimer's disease (AD) is an autosomal dominant disorder characterized by memory impairment and multiple cognitive deficits which occurs in mid to late life. Early onset AD has been associated with mutations in three genes, of which presenilin 1 (PS1) mutations are the most frequent. We sequenced the open reading frame from genomic DNA of a series of 21 early onset AD (AD3) UK families in which there were at least two affected individuals in two or more generations with a diagnosis of probable or definite AD. We found PS1 mutations in six of these families with no sequence variation in the remaining 15. The six families contained between them five different mutations of which two, I143F and P436S, have not been found elsewhere. I143F shows incomplete penetration within the affected family. P436S is the most carboxy-terminal presenilin 1 mutation reported to date.

Alzheimer Disease↗
PubMed1999

Molecular biology of prion propagation.

The occurrence of new variant Creutzfeldt-Jakob disease and the experimental confirmation that it is caused by the same prion strain as BSE has dramatically highlighted the need for a precise understanding of the molecular basis of prion propagation. The molecular basis of prion-strain diversity, previously a major challenge to the protein-only model, is now becoming clearer. The conformational change thought to be central to prion propagation, from a predominantly alpha-helical fold to one predominantly comprising beta-structure, can now be reproduced in vitro, and the ability of beta-PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation. These and other advances in the fundamental biology of prion propagation are leading to prion diseases becoming arguably the best understood of the neurodegenerative conditions and strategies for the development of rational therapeutics are becoming clearer.

Animals↗
PubMed1999

Structural mobility of the human prion protein probed by backbone hydrogen exchange.

Prions, the causative agents of Creutzfeldt-Jacob Disease (CJD) in humans and bovine spongiform encephalopathy (BSE) and scrapie in animals, are principally composed of PrPSc, a conformational isomer of cellular prion protein (PrPC). The propensity of PrPC to adopt alternative folds suggests that there may be an unusually high proportion of alternative conformations in dynamic equilibrium with the native state. However, the rates of hydrogen/deuterium exchange demonstrate that the conformation of human PrPC is not abnormally plastic. The stable core of PrPC has extensive contributions from all three alpha-helices and shows protection factors equal to the equilibrium constant for the major unfolding transition. A residual, hyper-stable region is retained upon unfolding, and exchange analysis identifies this as a small nucleus of approximately 10 residues around the disulfide bond. These results show that the most likely route for the conversion of PrPC to PrPSc is through a highly unfolded state that retains, at most, only this small nucleus of structure, rather than through a highly organized folding intermediate.

Circular Dichroism↗
PubMed1999

Strain-specific prion-protein conformation determined by metal ions.

In animals infected with a transmissible spongiform encephalopathy, or prion disease, conformational isomers (known as PrPSc proteins) of the wild-type, host-encoded cellular prion protein (PrPc) accumulate. The infectious agents, prions, are composed mainly of these conformational isomers, with distinct prion isolates or strains being associated with different PrPSc conformations and patterns of glycosylation. Here we show that two different human PrPSc types, seen in clinically distinct subtypes of classical Creutzfeldt-Jakob disease, can be interconverted in vitro by altering their metal-ion occupancy. The dependence of PrPSc conformation on the binding of copper and zinc represents a new mechanism for post-translational modification of PrP and for the generation of multiple prion strains, with widespread implications for both the molecular classification and the pathogenesis of prion diseases in humans and animals.

Binding Sites↗