Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: New insights into the molecular underpinnings of prion infectivity

Abstract

Prion diseases, or transmissible spongiform encephalopathies, have revealed the bewildering phenomenon of transmissibility in neurodegenerative diseases. Hence, the experimental transmissibility of prion-like neurodegenerative diseases via template directed misfolding has become the focus of intense research. Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited prion disease associated with mutations in the prion protein gene. However, with the exception of a few GSS cases with P102L mutation characterized by co-accumulation of protease-resistant PrP core (PrPres) of ∼21 kDa, attempts to transmit to rodents GSS associated to atypical misfolded prion protein with ∼8 kDa PrPres have been unsuccessful. As a result, these GSS subtypes have often been considered as non-transmissible proteinopathies rather than true prion diseases. In a recent study we inoculated bank voles with GSS cases associated with P102L, A117V and F198S mutations and found that they transmitted efficiently and produced distinct pathological phenotypes, irrespective of the presence of 21 kDa PrPres in the inoculum. This study demonstrates that GSS is a genuine prion disease characterized by both transmissibility and strain variation. We discuss the implications of these findings for the understanding of the heterogeneous clinic-pathological phenotypes of GSS and of the molecular underpinnings of prion infectivity.

Variable Protease-Sensitive Prionopathy Transmission to Bank Voles

“…Homogenate was inoculated into the cerebrum of 205 bank voles according to previously described procedures ( 16 ). The bank vole brains were processed for histopathology, immunohistochemistry, lesion profiles, and paraffin-embedded tissue (PET) blots according to previously reported procedures ( 15 ). Western blot was performed according to Notari et al ( 19 ).…”

“…The bank vole, a small rodent resembling the mouse with which it shares the entire sequence of normal PrP or PrP C except for 8 aa, but whose sequence differs from human PrPC by 15 aa, has recently emerged as a particularly permissive host. Bank voles and transgenic mice expressing bank vole PrP C have been successfully infected after challenge with human and animal prion diseases that are hard to transmit even to recipients expressing homologous PrP C ( 15 – 18 ).…”

Proteinase K resistant cores of prions and amyloids

“…The internal core of Sup35 can propagate on wild-type Sup35 in vitro, but is rapidly replaced by the N-terminal core in yeast cells. Similarly, the 8-kDa GSS core was not infectious for mice with wild-type PrP, with the exception of few GSS cases with P102L mutation, where PrP Sc was present simultaneously in the 8 kDa and 21 kDa forms [68,69] It was noted that octapeptide repeats in the N-terminal region of PrP, PHGGGWGQ, are fairly similar to nonapeptide repeats within prion domain of yeast Sup35, PQGGYQQYN [70], and this similarity could be significant. Deletion of one or more repeats from Sup35 interferes with [PSI + ] propagation [71,72], but replacement of the missing repeat with PrP repeat restores the ability to propagate [PSI + ] [71].…”

Characterization of mutations in <em>PRNP</em> (prion) gene and their possible roles in neurodegenerative diseases

“… 106 – 108 The pathogenic mechanism of A117V might be associated with the abnormal ctm region of PrP protein and could cause stress in the ER. 106 – 109 …”