Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy


The E200K mutation is the most frequent prion protein gene (PRNP) mutation detected worldwide that is associated with Creutzfeldt-Jakob disease (CJD) and thought to have overlapping features with sporadic CJD, yet detailed neuropathological studies have not been reported. In addition to the prion protein, deposition of tau, α-synuclein, and amyloid-β has been reported in human prion disease. To describe the salient and concomitant neuropathological alterations, we performed a systematic clinical, neuropathological, and biochemical study of 39 individuals carrying the E200K PRNP mutation originating from different European countries. The most frequent clinical symptoms were dementia and ataxia followed by myoclonus and various combinations of further symptoms, including vertical gaze palsy and polyneuropathy. Neuropathological examination revealed relatively uniform anatomical pattern of tissue lesioning, predominating in the basal ganglia and thalamus, and also substantia nigra, while the deposition of disease-associated PrP was more influenced by the codon 129 constellation, including different or mixed types of PrPres detected by immunoblotting. Unique and prominent intraneuronal PrP deposition involving brainstem nuclei was also noted. Systematic examination of protein depositions revealed parenchymal amyloid-β in 53.8%, amyloid angiopathy (Aβ) in 23.1%, phospho-tau immunoreactive neuritic profiles in 92.3%, neurofibrillary degeneration in 38.4%, new types of tau pathology in 33.3%, and Lewy-type α-synuclein pathology in 15.4%. TDP-43 and FUS immunoreactive protein deposits were not observed. This is the first demonstration of intensified and combined neurodegeneration in a genetic prion disease due to a single point mutation, which might become an important model to decipher the molecular interplay between neurodegeneration-associated proteins.

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This study was performed in the frame of the EU FP6 Project Neuroscreen LSHB-CZ-2006-037719 contract No. 037719. We are grateful for the technical assistance of Irene Leisser, Gerda Ricken, Lenkeine Marianna, Katalin Ress, Rachel Plantier, Françoise Didier, and for the kind cooperation of collegues and families of patients supporting our Surveillance systems. RV is a senior clinical investigator of the Research Foundation-Flanders. LL was supported by a grant of the Hungarian Scientific Research Fund (OTKA-NK78012).

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Correspondence to Gabor G. Kovacs.

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Supplementary Figure 1. Detailed anatomical mapping of lesions scores and anatomical correlations of PrP immunoreactivities in different subgroups of patients with E200K genetic CJD. a. Regional distribution of mean scores (+ standard error) of spongiform change and neuronal loss/gliosis in E200K genetic CJD cases grouped according to the codon 129 polymorphism. Summarized results of regions (cortical, hippocampal, basal ganglia and thalamus, brainstem and cerebellum) are indicated with bars. b. Graphic representation of regional differences of PrP immunoreactive patterns in E200K genetic CJD cases with MM or MV at codon 129. Cortical regions are represented as 100% and other regions are compared to the value of the cortical region to show whether their involvement is more or less prominent as in cortical areas (for details of regions see a). c. Mean (+ standard error) scores of intraneuronal PrP immunoreactivity in different anatomical regions in cases showing this pattern. (TIFF 7847 kb)

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Kovacs, G.G., Seguin, J., Quadrio, I. et al. Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy. Acta Neuropathol 121, 39–57 (2011).

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  • Alpha-synuclein
  • Amyloid-beta
  • Prion protein
  • Tau
  • Neurodegeneration