Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann–Sträussler–Scheinker disease

Abstract

The clinicopathological phenotype of the Gerstmann-Sträussler-Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of Ϸ21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt-Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and ''synaptic'' pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion diseases largely depends on the type of PrP-res fragment that forms in vivo. Because the formation of PrP-res fragments of 7-8 kDa with ragged N and C termini is not a feature of Creutzfeldt-Jakob disease or fatal familial insomnia but appears to be shared by most GSS subtypes, it may represent a molecular marker for this disorder.

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

“…Small, approximately 7-15 kDa, PK resistant fragments have previously been detected in human prion brain tissue (and as illustrated by Fig. 6a), particularly in the inherited Gerstmann-Sträussler-Scheinker (GSS) disease cases [75,76], although these are typically characterized as both N-and C-terminally truncated, and are therefore not the C3 species we describe. There is published evidence of small far-C-terminal PK resistant fragments in sporadic CJD, but not control brain tissue [77], which the authors designate as PrP-CTF12/13 to reflect their approximate size.…”

Structural Properties of Gerstmann-Sträussler-Scheinker Disease Amyloid Protein

“…The 18 -19-and 8-kDa peptides are N-and C-terminal truncated, as deduced by their antigenic profile, and are unglycosylated, likely representing amyloid protein precursors (15). Similar low molecular weight fragments have been detected in GSS patients with other PRNP mutations and are also present in areas without amyloid deposits, suggesting that regional factors feature in amyloidogenesis (15)(16)(17). Of note, the PrP region spanning residues 89 -140 is an integral part of the minimal sequence which sustains prion replication (18,19), suggesting that it plays a central role in the conformational transition of PrP C into PrP Sc and in PrP Sc propagation.…”

Prion disease genetics

“…This diversity may be partly constrained by PrP primary structure, known as the conformation selection hypothesis. 8 Diversity of PrP conformation within a single pedigree may account for phenotypic variability if different pathological conformers have differing toxicity or neuropathological targeting (Piccardo et al, 30 Parchi et al, 31 and our own observations). A related issue is the possibility of a variable contribution to the disease process from the product of the wild-type PRNP allele (Chen et al 32 and our own observations).…”