Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

Abstract

Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrPSc), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as “isolates” causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrPSc distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective.

CSF SerpinA1 in Creutzfeldt–Jakob disease and frontotemporal lobar degeneration

“…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 . Another possible hypothesis could relate the different SerpinA1 patterns to the kinetics of the disease even if we did not find significant associations between the time from onset to LP and SerpinA1 signal in each CJD molecular subgroup.…”

“…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. 25 Another possible hypothesis could relate the different SerpinA1 patterns to the kinetics of the disease even if we did not find significant associations between the time from onset to LP and SerpinA1 signal in each CJD molecular subgroup. Moreover, given that SerpinA1 might play an anti-inflammatory role by attenuating microglial activity, [3][4][5] the increase in total SerpinA1 and in some of its isoforms in sCJD MM(V)1 compared to sCJD linked to PrP Sc type 2 could be considered a stronger early attempt to balance the developing neuroinflammation/neurodegeneration that progresses faster in the former group than in the latter.…”

Proteinase K resistant cores of prions and amyloids

“…The first group includes Creutzfeldt-Jakob disease (CJD) of any origin (sporadic, familial, iatrogenic and variant CJD), fatal familial insomnia (FFI) and kuru. The second group includes Gerstmann-Sträussler-Scheinker disease (GSS) and variably protease-sensitive prionopathy (VPSPr) [19].…”

Molecular dynamics simulation of local structural models of PrPSc reveals how codon 129 polymorphism affects propagation of PrPSc

“…The higher stability of the CN-truncated M129 Type-1 than that of CN-truncated V129 Type-2 β-arch ( Fig 4G vs 5C ) was unexpected. We had anticipated the opposite, because heterozygous CJD cases tend to exhibit more features of V129-homozygous CJD, with 19-kDa core and plaque-type depositions [5][35], suggesting a possibility that V129-PrP predominates the phenotype because it is more amyloid-prone. On the other hand, the higher stability of the M129 β-arch seemed consistent with the higher relative risk of sporadic CJD in M129-homozygous population than the V129-homozygous [36].…”