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01-01-2011 | Original Paper

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

Authors: Gabor G. Kovacs, Jérémie Seguin, Isabelle Quadrio, Romana Höftberger, István Kapás, Nathalie Streichenberger, Anne Gaëlle Biacabe, David Meyronet, Raf Sciot, Rik Vandenberghe, Katalin Majtenyi, Lajos László, Thomas Ströbel, Herbert Budka, Armand Perret-Liaudet

Published in: Acta Neuropathologica | Issue 1/2011

Abstract

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 PrP^res 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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Title: Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy
Authors: Gabor G. Kovacs
Jérémie Seguin
Isabelle Quadrio
Romana Höftberger
István Kapás
Nathalie Streichenberger
Anne Gaëlle Biacabe
David Meyronet
Raf Sciot
Rik Vandenberghe
Katalin Majtenyi
Lajos László
Thomas Ströbel
Herbert Budka
Armand Perret-Liaudet
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 1/2011
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-010-0713-y

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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