Genetic Creutzfeldt-Jakob disease associated with the E200K mutation

Characterization of a complex proteinopathy

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

Research output: Contribution to journalArticle

68 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)39-57
Number of pages19
JournalActa Neuropathologica
Volume121
Issue number1
DOIs
Publication statusPublished - Jan 2011

Fingerprint

Creutzfeldt-Jakob Syndrome
Synucleins
Prion Diseases
Amyloid
Mutation
RNA-Binding Protein FUS
Pathology
Inborn Genetic Diseases
Polyneuropathies
Substantia Nigra
Basal Ganglia
Thalamus
Point Mutation
Immunoblotting
Codon
Paralysis
Genes
Brain Stem
Dementia
Proteins

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Kovacs, G. G., Seguin, J., Quadrio, I., Höftberger, R., Kapás, I., Streichenberger, N., ... Perret-Liaudet, A. (2011). Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: Characterization of a complex proteinopathy. Acta Neuropathologica, 121(1), 39-57. https://doi.org/10.1007/s00401-010-0713-y

Genetic Creutzfeldt-Jakob disease associated with the E200K mutation : Characterization of a complex proteinopathy. / Kovacs, Gabor G.; Seguin, Jérémie; Quadrio, Isabelle; Höftberger, Romana; Kapás, István; Streichenberger, Nathalie; Biacabe, Anne Gaëlle; Meyronet, David; Sciot, Raf; Vandenberghe, Rik; Majtényi, K.; László, L.; Ströbel, Thomas; Budka, Herbert; Perret-Liaudet, Armand.

In: Acta Neuropathologica, Vol. 121, No. 1, 01.2011, p. 39-57.

Research output: Contribution to journalArticle

Kovacs, GG, Seguin, J, Quadrio, I, Höftberger, R, Kapás, I, Streichenberger, N, Biacabe, AG, Meyronet, D, Sciot, R, Vandenberghe, R, Majtényi, K, László, L, Ströbel, T, Budka, H & Perret-Liaudet, A 2011, 'Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: Characterization of a complex proteinopathy', Acta Neuropathologica, vol. 121, no. 1, pp. 39-57. https://doi.org/10.1007/s00401-010-0713-y
Kovacs, Gabor G. ; Seguin, Jérémie ; Quadrio, Isabelle ; Höftberger, Romana ; Kapás, István ; Streichenberger, Nathalie ; Biacabe, Anne Gaëlle ; Meyronet, David ; Sciot, Raf ; Vandenberghe, Rik ; Majtényi, K. ; László, L. ; Ströbel, Thomas ; Budka, Herbert ; Perret-Liaudet, Armand. / Genetic Creutzfeldt-Jakob disease associated with the E200K mutation : Characterization of a complex proteinopathy. In: Acta Neuropathologica. 2011 ; Vol. 121, No. 1. pp. 39-57.
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