Recent advances in the histo‐molecular pathology of human prion disease

Abstract

Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be infectious, refers to PrP Sc , a misfolded isoform of the cellular prion protein (PrP C ) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrP Sc , has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt-Jakob disease, by far the most common, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann-Sträussler-Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrP Sc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrP Sc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo-molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co-pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrP Sc aggregates.

CSF SerpinA1 in Creutzfeldt–Jakob disease and frontotemporal lobar degeneration

“…Most interestingly, CJD cases linked to PrP Sc type 1, such as sCJD MM(V)1, VV1, and gCJD E200K‐129M types, differed in total and single peak area from both controls and cases linked to PrP Sc type 2 (VV2, MV2K, and MM2C groups). It is well established that the type of PrP Sc largely determines the distinctive histopathological and molecular features of sCJD . In this respect, the different post‐translational modifications of SerpinA1 between sCJD subtypes may represent a PrP Sc ‐specific or a strain pathogenetic event.…”

“…It is well established that the type of PrP Sc largely determines the distinctive histopathological and molecular features of sCJD. 24 In this respect, the different post-translational modifications of SerpinA1 between sCJD subtypes may represent a PrP Sc -specific or a strain pathogenetic event. Accordingly, the lack of difference in SerpinA1 profile between sCJD MM(V)1 and gCJD E200K-129M or between sCJD VV2 and sCJD MV2K are consistent with the notion that these couples of prion variants are, respectively, linked to the same PrP Sc type and strain.…”

Proteinase K resistant cores of prions and amyloids

“…GSS differs from CJD and FFI by slower disease progression and amyloid deposition rather than spongiform change of brain tissue [21]. This difference might be due to a much smaller PrP core of 7-8 kDa observed in GSS, which does not include the C-terminal region, and thus does not include the GPI anchor and glycoside chains.…”

Gerstmann-Sträussler-Scheinker disease ( PRNP p.D202N) presenting with atypical parkinsonism

“…It is well established that the methionine (M)/valine(V) polymorphism at PRNP codon 129 strongly modulates the disease phenotype of human prion disease. 6 In GSS-p.D202N, the mutation cosegregated with V129. Indeed, valine homozygosity at codon 129 was documented in 3 patients, and the mutation was in cis with valine in a fourth case (table e-1, links.…”