期刊
VIRUSES-BASEL
卷 14, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/v14020367
关键词
VPSPr; prion disease; PRNP; protein misfolding; scrapie; amyloid; real-time quaking-induced conversion; RT-QuIC; Creutzfeldt-Jakob disease; CJD
类别
Variably protease-sensitive prionopathy is a rare and underestimated prion disease with diverse and often non-specific clinical and pathological features. The host genetic background, particularly the PRNP codon 129 genotype, plays a significant role in phenotypic modulation. The sensitivity of pathological prion protein to proteinase K digestion varies based on different genotypes, leading to distinct PrPSc profiles and cerebral/cerebellar PrP mini-plaque patterns.
Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (PRNP). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the PRNP codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrPSc), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrPSc profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV).
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