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

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.

journal_name

Acta Neuropathol

journal_title

Acta neuropathologica

authors

Kovacs GG,Seguin J,Quadrio I,Höftberger R,Kapás I,Streichenberger N,Biacabe AG,Meyronet D,Sciot R,Vandenberghe R,Majtenyi K,László L,Ströbel T,Budka H,Perret-Liaudet A

doi

10.1007/s00401-010-0713-y

subject

Has Abstract

pub_date

2011-01-01 00:00:00

pages

39-57

issue

eissn

0001-6322

issn

1432-0533

journal_volume

121

pub_type

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