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Biomedical subjects

J Collinge

Publications and source records attributed to J Collinge.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mossy fibre reorganization in the hippocampus of prion protein null mice.

Mice lacking prion protein (PrP-null) are resistant to transmissible spongiform encephalopathies. However, the normal functions of this highly conserved protein remain controversial. This study examines whether PrP-null mice develop normal neuronal pathways, specifically the mossy fibre pathway, within the hippocampus. Timm stained hippocampal sections from the PrP-null group had more granules than the controls in: the granule cell layer, the inner molecular layer of the dentate gyrus, and the infrapyramidal region of CA3. This resembles the mossy fibre collateral and terminal sprouting seen in certain epilepsies. The abnormal connectivity might be predicted to promote epileptiform activity, but extracellular electrophysiological recordings from the granule cell layer revealed a reduced excitability in the PrP-null group, both with and without blockade of GABA(A) receptor-mediated inhibition. We propose that reorganization of neuronal circuity is a feature of PrP-null mice.

Analysis of Variance↗
PubMed1997

Conformational properties of the prion octa-repeat and hydrophobic sequences.

We have used circular dichroism to study synthetic peptides from two important regions of the prion protein: the N-terminal octa-repeat domain and a highly conserved hydrophobic section. Our results show that the octa-repeat sequence in free solution can adopt a non-random, extended conformation with properties similar to the poly-L-proline type II left-handed helix. We also show that the conformation can be changed by temperature, organic solvents (e.g. acetonitrile) and on binding to phospholipid vesicles. We compared CD data from two peptides corresponding to the hydrophobic region between residues 106 and 136 which contained either methionine or valine at position 129. This variation represents a common polymorphism in humans which has been shown to influence predisposition towards iatrogenic and sporadic CJD. There was no detectable difference between the CD spectra of these peptides irrespective of the solvent conditions we used.

Amino Acid Sequence↗
PubMed1997

Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.

OBJECTIVE: To describe symptoms, signs, neuroimaging results, and neuropathologic findings in patients from a family with chromosome 17q21-linked autosomal dominant frontotemporal dementia. DESIGN: Multiple case report with genetic investigations. SUBJECTS: The disease was observed in a Swedish family and documented in 3 generations. Four siblings are described in this article. RESULTS: A rapidly progressive dementia with genetic linkage to chromosome 17q21 was observed. The mean age of onset was 51 years and the average duration of disease to death was 3 years. Two patients started with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia and akinesia and muscular rigidity, and in 1 patient reckless driving was the first symptom. Loss of spontaneous speech developed later in all patients and emotional bluntness in 3 of the patients. Cerebral perfusion was decreased in the frontal areas in all patients. In the person with apraxia as the onset symptom, the cerebral blood flow was also diminished in the left hemisphere, where a slight atrophy was detected on magnetic resonance imaging scans. At the postmortem examination, slight gliosis of the parietal lobes was observed in this patient. In all patients there was a frontocentral degeneration of the cortex with discrete microvacuolation and gliosis. CONCLUSION: Clinical features of frontotemporal dementia, parkinsonism, an early age of onset, a rapid disease progression, and variable onset symptoms were seen in these patients. Two other clinically distinct diseases, dementia with pallido-ponto-nigral degeneration and a disinhibition-dementia-parkinsonism-amyotrophy complex, have recently been mapped to chromosome 17q21. In the family described in this article, genetic linkage was detected to the same region, suggesting the possibility that these diseases may originate from pathogenic mutations in the same gene.

Chromosomes, Human, Pair 17↗
PubMed1997

Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor.

Sixteen affected individuals are described from two families with early onset autosomal dominant familial Alzheimer's disease. A mutation at codon 139 in the presenilin 1 gene on chromosome 14 results in a methionine to valine substitution which cosegregates with the disease in these families. Onset of dementia was before the age of 50 years in all individuals. The ages at onset within each family were tightly clustered but were significantly different between the families; this difference could not be accounted for by apolipoprotein E status and suggests the existence of a further genetic factor that modifies age at disease onset. The pattern of cognitive decline was similar in both families: early memory loss (initially selective for verbal memory in some individuals) was followed soon after by loss of arithmetic skills while naming and object perception skills were relatively preserved. A speech production deficit was observed in three members of one family but not in the other. Seizures were common and usually predated by myoclonic jerks by a number of years. Serial MRIs showed progressive cortical atrophy with periventricular white matter change appearing 3-4 years into the disease. PET revealed parieto-temporal hypometabolism in all individuals scanned. The diagnosis of Alzheimer's disease was confirmed with typical histopathology in one individual from each family.

Adult↗
PubMed1997

Human prion diseases and bovine spongiform encephalopathy (BSE).

Prion diseases are transmissible neurodegenerative disorders which affect a range of mammalian species. In humans they can be inherited and sporadic as well as acquired by exposure to human prions. Prions appear to be composed principally of a conformational isomer of host-encoded prion protein and propagate by recruitment of cellular prion protein. Recent evidence argues that prion protein can also encode disease phenotypes by differences in its conformation and glycosylation. Such molecular analysis of prion strains suggests that new variant Creutzfeldt-Jakob disease is caused by BSE exposure. The novel biology of prion propagation may not be unique to these rare degenerative brain diseases.

Animals↗
PubMed1996

Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD.

Strains of transmissible spongiform encephalopathies are distinguished by differing physicochemical properties of PrPSc, the disease-related isoform of prion protein, which can be maintained on transmission to transgenic mice. 'New variant' Creutzfeldt-Jakob disease (CJD) has strain characteristics distinct from other types of CJD and which resemble those of BSE transmitted to mice, domestic cat and macaque, consistent with BSE being the source of this new disease. Strain characteristics revealed here suggest that the prion protein may itself encode disease phenotype.

Animals↗
PubMed1996

Hippocampal slices from prion protein null mice: disrupted Ca(2+)-activated K+ currents.

The intrinsic properties of hippocampal CA1 pyramidal cells were examined in mice lacking prion protein (PrP-null). The resting potentials, time constants, amplitude of the medium afterhyperpolarization (AHP) and spike firing accommodation did not differ from the control group. The PrP-null group differed in having lower input resistances, a lack of the late AHP and of a charybdotoxin-sensitive summated AHP. We propose that CA(2+)-activated K+ currents, in particular IAHP, are disrupted in PrP-null mice.

Action Potentials↗