Objective The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with “variably protease-sensitive prionopathy” (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.
Objective:To compare the respective efficiency of CSF tau (quantitative) and CSF 14-3-3 protein (qualitative) in the diagnosis of prion disease. Methods:We made measurements on 420 live subjects, who subsequently underwent a postmortem neuropathology examination, including protein chemistry, immunohistochemistry, and histology. We performed tau by ELISA. We detected 14-3-3 protein by Western blot. Both assays were optimized for maximum efficiency (accuracy).
Phenotypic heterogeneity of sporadic Creutzfeldt-Jakob disease (CJD) has been linked to biochemically distinct types of the protease-resistant form of the prion protein (type 1 and type 2 PrP(Sc)). We investigated 14 cases of sporadic CJD and found that both type 1 and type 2 PrP(Sc) coexisted in 5 subjects. The distinct PrP(Sc) isoforms were associated with different patterns of PrP deposition and severity of spongiform changes, suggesting that the PrP(Sc) type plays a central role in determining the neuropathologic profile of CJD.
The prion protein (PrP) is best known for its association with prion diseases. However, a controversial new role for PrP in Alzheimer disease (AD) has recently emerged. In vitro studies and mouse models of AD suggest that PrP may be involved in AD pathogenesis through a highly specific interaction with amyloid- (A42) oligomers. Immobilized recombinant human PrP (huPrP) also exhibited high affinity and specificity for A42 oligomers. Here we report the novel finding that aggregated forms of huPrP and A42 are co-purified from AD brain extracts. Moreover, an anti-PrP antibody and an agent that specifically binds to insoluble PrP (iPrP) co-precipitate insoluble A from human AD brain. Finally, using peptide membrane arrays of 99 13-mer peptides that span the entire sequence of mature huPrP, two distinct types of A binding sites on huPrP are identified in vitro. One specifically binds to A42 and the other binds to both A42 and A40. Notably, A42-specific binding sites are localized predominantly in the octapeptide repeat region, whereas sites that bind both A40 and A42 are mainly in the extreme N-terminal or C-terminal domains of PrP. Our study suggests that iPrP is the major PrP species that interacts with insoluble A42 in vivo. Although this work indicated the interaction of A42 with huPrP in the AD brain, the pathophysiological relevance of the iPrP/A42 interaction remains to be established. Alzheimer disease (AD)2 is the leading cause of dementia in the elderly and the most common neurodegenerative disorder. The underlying pathology in AD seems to be associated with the accumulation of soluble and insoluble aggregated species of the amyloid- (A) peptide in the brain (1). However, the mechanisms underlying A deposition and neurotoxicity remain poorly understood. The cellular prion protein (PrP C ) is a glycoprotein highly expressed in the brain, and best known for its association with prion diseases. These are unique neurodegenerative disorders with an infectious, sporadic or genetic etiology, and which are characterized by deposition of misfolded, pathological PrP (PrP Sc ) in the brain (2). Interestingly, a recent interpretation of early and newer observations suggests that PrP C may play a role in the pathogenesis of AD (3). Epidemiological studies suggest that the Met/Val polymorphism at residue 129 in PrP modulates the number of A deposits (4). Also, pathological evidence indicates that PrP deposits often accompany A plaques in AD (5-7). Moreover, transgenic mice expressing mutant amyloid precursor protein (APP) and overexpressing hamster PrP C present an exacerbated A plaque burden (8). The circumstantial evidence of an association between PrP and A was greatly strengthened by the recent finding that PrP was the protein that most strongly supported the binding of cells to soluble A42 oligomers in a screen of 225,000 murine clones (9). The authors also showed that although A42 oligomers suppressed long-term potentiation (LTP) in CA1 hippocampal neurons in mouse brain slices, LTP inhibitio...
To report the clinical, genetic, neuroimaging, and neuropathologic studies of patients with the hereditary cerebral hemorrhage with amyloidosis linked to the APP E693K mutation. Design: Case series. Clinical details and laboratory results were collected by direct evaluation and previous medical records. DNA analysis was carried out in several affected subjects and healthy individuals. Neuropathologic examination was performed in 2 subjects.
Variably protease-sensitive prionopathy (VPSPr) is a novel disease involving the prion protein (PrP) that has clinical similarities with non-Alzheimer's dementias especially frontotemporal dementia, diffuse Lewis body disease, and normal pressure hydrocephalus. VPSPr can be distinguished from sporadic Creutzfeldt-Jakob disease (sCJD) especially for the characteristics of the abnormal PrP. Furthermore, although VPSPr like sCJD affects patients with the three PrP genotypes as determined by the common methionine/valine polymorphism, the allelic prevalence is very different in the two diseases. These findings suggest that VPSPr is basically different from classical prion diseases such as sCJD being perhaps more akin to other neurodegenerative dementias.
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