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Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of PrP gene
J J Hauw1, V Sazdovitch, J L Laplanche
1Raymond Escourolle Neuropathology Laboratory, Pitié-Salpêtrière Hospital, Paris, France. jean-jazques.hauw@psl.ap-hop-paris.fr
Objectives:
To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease.
Background:
Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques.
Methods:
The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998.
Results:
Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety.
Conclusions:
Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.
Insights
The prion protein gene polymorphism at codon 129 influences sporadic Creutzfeldt-Jakob disease (CJD) presentation. Valine genotype increases abnormal prion protein, while methionine/valine genotype promotes plaque formation.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal neurodegenerative prion disease.
- It involves misfolding of the prion protein (PrP) and various PrP deposits, including amyloid plaques.
- The methionine/valine (Met/Val) polymorphism at codon 129 of the PrP gene is a known risk factor.
Purpose of the Study:
- To investigate the role of the Met/Val polymorphism at codon 129 of the PrP gene.
- To determine its contribution to neuropathologic patterns in sporadic CJD.
- To elucidate its impact on lesion development mechanisms.
Main Methods:
- Semiquantitative assessment of neuropathologic lesions.
- Prion protein (PrP) immunolabeling.
- Analysis of 70 deceased patients with sporadic CJD (39 Met/Met, 11 Met/Val, 20 Val/Val) in France (1994-1998).
Main Results:
- Met/Met cases showed mild lesions, low PrP load, and few non-amyloid deposits.
- Met/Val cases exhibited marked lesions, high PrP load, and numerous amyloid plaques.
- Val/Val cases presented severe lesions, high PrP load, non-amyloid deposits, and rare amyloid plaques, with distinct pathology in younger patients.
Conclusions:
- Codon 129 polymorphism significantly modulates the phenotype of sporadic CJD.
- The Val genotype is associated with increased proteinase-resistant PrP.
- The Met/Val genotype facilitates PrP aggregation into amyloid plaques.