title: Allelic origin of protease-sensitive and protease-resistant prion protein isoforms in Gerstmann-Sträussler-Scheinker disease with the P102L mutation.
abstract: Gerstmann-Sträussler-Scheinker (GSS) disease is a dominantly inherited prion disease associated with point mutations in the Prion Protein gene. The most frequent mutation associated with GSS involves a proline-to-leucine substitution at residue 102 of the prion protein, and is characterized by marked variability at clinical, pathological and molecular levels. Previous investigations of GSS P102L have shown that disease-associated pathological prion protein, or PrP(Sc), consists of two main conformers, which under exogenous proteolysis generates a core fragment of 21 kDa and an internal fragment of 8 kDa. Both conformers are detected in subjects with spongiform degeneration, whereas only the 8 kDa fragment is recovered in cases lacking spongiosis. Several studies have reported an exclusive derivation of protease-resistant PrP(Sc) isoforms from the mutated allele; however, more recently, the propagation of protease-resistant wild-type PrP(Sc) has been described. Here we analyze the molecular and pathological phenotype of six GSS P102L cases characterized by the presence of 21 and 8 kDa PrP fragments and two subjects with only the 8 kDa PrP fragment. Using sensitive protein separation techniques and Western blots with antibodies differentially recognizing wild-type and mutant PrP we observed a range of PrP(Sc) allelic conformers, either resistant or sensitive to protease treatment in all investigated subjects. Additionally, tissue deposition of protease-sensitive wild-type PrP(Sc) molecules was seen by conventional PrP immunohistochemistry and paraffin-embedded tissue blot. Our findings enlarge the spectrum of conformational allelic PrP(Sc) quasispecies propagating in GSS P102L thus providing a molecular support to the spectrum of disease phenotypes, and, in addition, impact the diagnostic role of PrP immunohistochemistry in prion diseases.
authors.affiliation: Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Verona, Italy. salvatore.monaco@univr.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Monaco
authors.forename: Michele
authors.initials: M
authors.lastname: Fiorini
authors.forename: Alessia
authors.initials: A
authors.lastname: Farinazzo
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.forename: Matteo
authors.initials: M
authors.lastname: Gelati
authors.forename: Pedro
authors.initials: P
authors.lastname: Piccardo
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanusso
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D002499:Centrifugation, Density Gradient; D005260:Female; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007525:Isoelectric Focusing; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010447:Peptide Hydrolases / Q000378:metabolism*; D010641:Phenotype; D017354:Point Mutation; D049268:Positron-Emission Tomography / Q000379:methods; D018620:PrPSc Proteins / Q000235:genetics*; D011487:Protein Conformation; D059748:Proteolysis; D013395:Sucrose / Q000737:chemistry
chemical_list: D018620:PrPSc Proteins; D013395:Sucrose; D010447:Peptide Hydrolases