Phenotypic Variability of Gerstmann-Straussler-Scheinker Disease is Associated with Prion Protein Heterogeneity

Abstract

Gerstmann-Sträussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.

Prion Proteins with Different Conformations Accumulate in Gerstmann-Sträussler-Scheinker Disease Caused by A117V and F198S Mutations

“…It is important to note that the amount of PrP sc in the patients (1 to 5) reported here is significantly smaller than that found in other GSS variants. 11,13 In agreement with the results presented here, recent studies in an Alsatian patient with GSS A117V 18 showed that the major component of amyloid fibrils was a ϳ7-kd peptide with ragged N terminus starting mainly at G 88 and G 90 . 18 The 14-and 7-kd bands, seen in GSS A117V (1 to 5), are detected by antibodies directed to the mid-region of PrP indicating that these fragments include the intact epitope recognized by mAb 3F4 consisting of residues 109 to 112.…”

“…3 GSS is caused by mutations P102L, P105L, A117V, G131V, F198S, D202N, Q212P, and Q217R in PRNP. 3,11,12 The pathological hallmark of GSS is the accumulation of PrP, with and without amyloid tinctorial properties, in the brain. 3 Our studies have shown that the pattern of PrP sc isoforms in the multiple GSS variants analyzed is different from that seen in CJD.…”

“…3 Our studies have shown that the pattern of PrP sc isoforms in the multiple GSS variants analyzed is different from that seen in CJD. [11][12][13] Patients with CJD present full-length and Ntruncated PrP fragments whereas patients with GSS present full-length as well as N-and C-terminal truncated PrP peptides. 10 -13,14,15 Previous studies showed that the amyloid subunit in GSS F198S is a 7-kd peptide with an N terminus at residue G 81 .…”

“…13 In GSS A117V, previous studies have been contradictory in terms of whether or not PK-resistant PrP is present. 11,19,20 The aims of the present study are to determine the biochemical characteristics of PrP in several patients and an asymptomatic carrier from two unrelated American families with PRNP A117V. 21,22 We analyzed brain homogenates, microsomal preparations, and purified PrP fractions.…”

“…Samples were resolved in 4 to 12% acrylamide gels and transferred to nitrocellulose membranes as described. 11,13 Membranes were probed with monoclonal antibody (mAb) 3F4. 27 Immunoblot analysis for PrP sc was done after digestion of the homogenates with PK (10 g/ml) for 1 hour at 37°C.…”