Prion protein genotype and pathological phenotype studies in sporadic Creutzfeldt‐Jakob disease

MacDonald, Simon T.; Sutherland, K.; Ironside, James W.

doi:10.1111/j.1365-2990.1996.tb01106.x

Cited by 53 publications

(35 citation statements)

References 19 publications

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“…Although the physiological function of PrP, if any, remains obscure, it may be that the maintenance of this polymorphism results from the selective pressure of prion diseases. There is evidence that the polymorphism affects susceptibility to sporadic (3,4) and acquired (5, 6) prion diseases and of features such as their age of onset and pathological presentation (7)(8)(9). Most strikingly, M129V heterozygotes appear to be relatively protected from sporadic, inherited, and infectious prion diseases in these studies.…”

mentioning

confidence: 71%

Molecular Heterosis of Prion Protein β-Oligomers

Tahiri-Alaoui

Sim

Caughey

et al. 2006

Journal of Biological Chemistry

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The gene encoding prion protein is polymorphic in human populations, with over 40% of native Europeans, for example, being heterozygous for the Met-129 and Val-129 alleles. The polymorphism affects both the incidence and the clinical presentation of a range of prion diseases, with heterozygotes generally showing the highest levels of resistance. It has been suggested that an earlier epidemic of prion diseases exerted balancing selection on the two alleles, and we have previously demonstrated that the two encoded proteins have potentially compensating tendencies to form amyloid and soluble ␤-oligomers, respectively, in vitro. More strikingly, here we demonstrate that mixed oligomers, composed of both allelic forms, show an extreme sluggishness in converting to amyloid in comparison with oligomers homogenous for either allele. It may be that this example of molecular heterosis in vitro provides the basis for maintenance of the polymorphism in the population and that ␤-oligomers represent a form of PrP sequestered from pathogenic amyloid formation in vivo.

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mentioning

confidence: 71%

Molecular Heterosis of Prion Protein β-Oligomers

Tahiri-Alaoui

Sim

Caughey

et al. 2006

Journal of Biological Chemistry

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“…In addition, harsh treatment with formic acid and autoclaving in the presence of HCl or guanidine chloride compromising to some extent the anatomical detail are required to increase PrP immunoreactivity (Kitamoto et al, 1992). Quantitative analyses of PrP immunoreactivity are possible (MacDonald et al, 1996) but require a strict control of variables such as the time and type of fixation, which significantly influence the intensity of the immunoreaction.…”

Section: Methods Of Studymentioning

confidence: 99%

Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia

Parchi

Capellari

2000

Microsc. Res. Tech.

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“…22 In addition, we and others demonstrated an influence on disease phenotype of a common methionine/ valine (MV) polymorphism at codon 129 in the PRNP. [22][23][24][25] To define the full spectrum of sCJD variants, and contribute to the understanding of pathogenesis and extent of strain variation in sCJD, we performed a detailed phenotypic and molecular analysis of 300 sCJD patients. Based on these studies, which represent the first comprehensive analysis of both molecular and clinicopathological features in a large series of patients, we propose a classification of sCJD into six distinct variants.…”

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confidence: 99%

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects

Parchi¹,

Giese²,

Capellari³

et al. 1999

Ann Neurol.

1,263

693

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Phenotypic heterogeneity in sporadic Creutzfeldt‐Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease‐resistant prion protein (PrPSc) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrPSc properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrPSc deposition. Seventy percent of subjects showed the classic CJD phenotype, PrPSc type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru‐plaque variants, associated to PrPSc type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrPSc type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrPSc type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants. Ann Neurol 1999;46:224–233

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Prion protein genotype and pathological phenotype studies in sporadic Creutzfeldt‐Jakob disease

Cited by 53 publications

References 19 publications

Molecular Heterosis of Prion Protein β-Oligomers

Molecular Heterosis of Prion Protein β-Oligomers

Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects

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