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.