Molecular basis of phenotypic variability in sporadc creudeldt‐jakob disease
Abstract
We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob…
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In our previous study on amyloid plaques in prion diseases, we demonstrated that kuru plaques morphologically and ultrastructurally resemble those characteristic of sporadic CJD subtype 3 according to the Parchi and Gambetti classification but are remarkably different from florid plaques in variant CJD and multicentric plaques in GSS.
“In our previous study on amyloid plaques encountered in prion diseases (71), we demonstrated that kuru plaques morphologically and ultrastructurally resemble those that are characteristic of sporadic CJD subtype 3 according to the Parchi and Gambetti classification (22) but were remarkably different from florid plaques in variant CJD and multicentric plaques in GSS.”
From Kuru (2012) · cites this paper as [22]
The latter kuru case is neuropathologically most similar to type 2 or 3 129 MV type of CJD of the Collinge et al classification or type 2 CJD of the Parchi et al classification.
“The latter case has been neuropathologically compared with known subtypes of CJD and it seems the most similar to type 2 or 3 129 MV type of CJD of the Collinge et al (80) classification or type 2 CJD of the Parchi et al (22) classification.”
From Kuru (2012) · cites this paper as [22]
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“In our previous study on amyloid plaques encountered in prion diseases (71), we demonstrated that kuru plaques morphologically and ultrastructurally resemble those that are characteristic of sporadic CJD subtype 3 according to the Parchi and Gambetti classification (22) but were remarkably different from florid plaque…”
BackgroundResultCystatin F is a biomarker of prion pathogenesis in mice
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Loss of Homeostatic Microglia Signature in Prion Diseases
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“The molecular basis for this phenotypic variability is defined by the distinct biochemical properties of the prion protein and an allelic variation in codon 129 (methionine or valine) of the prion protein gene (PRNP) [12,13].”
Background
- Authors
- Parchi, P., Castellani, R., Capellari, S., Ghetti, B., Young, K., Chen, S. G., Farlow, M., Dickson, D. W., Sima, A. A. F., Trojanowski, J. Q., Petersen, R. B., & Gambetti, P.
- Affiliations
- Case Western Reserve University (US)
- Indiana University Indianapolis (US)
- Albert Einstein College of Medicine (US)
- University of Pennsylvania (US)
- Indiana University School of Medicine (US)
- University of Michigan (US)
- Corresponding author
- Gambetti, Pierluigi
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 1996-06
- Volume
- 39
- Issue
- 6
- Pages
- 767-778
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2056426612
- Cited by
- 864
- References
- 1
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 24 · 2023: 20 · 2022: 20 · 2021: 27 · 2020: 26 · 2019: 19 · 2018: 23 · 2017: 19 · 2016: 23 · 2015: 13 · 2014: 23 · 2013: 31 · 2012: 29
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r37ag008155-10, 5r35ag008992-07)
- National Institute on Aging (AG 10133, P30AG010133, AG-08155, AG 08992)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- sporadic Creutzfeldt-Jakob disease, prion protein gene, codon 129 polymorphism, protease-resistant prion protein, prion strains, kuru plaques, clinicopathological classification, phenotypic variability
- MeSH terms
- Adult, Aged, Astrocytes, Brain, Codon, Female, Genotype, Glycosylation, Homozygote, Humans, Immunohistochemistry, Creutzfeldt-Jakob Syndrome, Male, Methionine, Middle Aged, Phenotype, Prions, Serine Endopeptidases, Blotting, Western, Endopeptidase K, Culture Techniques
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