Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein.
Inherited prion diseases are caused by PRNP coding mutations and display marked phenotypic heterogeneity within families segregating the same pathogenic mutation. A proline-to-leucine substitution at prion protein (PrP) residue 102 (P102L), classically associated with the Gerstmann-Sträussler-Scheinker (GSS) phenotype, also shows marked clinical and pathological heterogeneity, including patients with a Creutzfeldt-Jakob disease (CJD) phenotype. To date, this heterogeneity has been attributed to temporal and spatial variance in the propagation of distinct protease-resistant (PrP(Sc)) isoforms of mutant PrP. Here, using a monoclonal antibody that recognizes wild-type PrP, but not PrP 102L, we reveal a spectrum of involvement of wild-type PrP(Sc) in P102L individuals. PrP(Sc) isoforms derived from wild-type and mutant PrP are distinct both from each other and from those seen in sporadic and acquired CJD. Such differential propagation of disease-related isoforms of wild-type PrP and PrP 102L provides a molecular mechanism for generation of the multiple clinicopathological phenotypes seen in inherited prion disease.
Wadsworth
Jonathan D F
JD
MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery Queen Square, London, UK.
Joiner
Susan
S
Linehan
Jacqueline M
JM
Cooper
Sharon
S
Powell
Caroline
C
Mallinson
Gary
G
Buckell
Jennifer
J
Gowland
Ian
I
Asante
Emmanuel A
EA
Budka
Herbert
H
Brandner
Sebastian
S
Collinge
John
J
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008875:Middle Aged; D050505:Mutant Proteins / Q000032:analysis* / Q000276:immunology; D009154:Mutation; D010447:Peptide Hydrolases; D010641:Phenotype; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; D050505:Mutant Proteins; D011328:Prions; D020033:Protein Isoforms; D010447:Peptide Hydrolases