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Brain Advance Access published online on April 5, 2006
Brain, doi:10.1093/brain/awl076
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received November 24, 2005
Revised February 3, 2006
Accepted March 8, 2006

Article

Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein

Jonathan D. F. Wadsworth 1 *, Susan Joiner 1, Jacqueline M. Linehan 1, Sharon Cooper 1, Caroline Powell 1, Gary Mallinson 1, Jennifer Buckell 1, Ian Gowland 1, Emmanuel A. Asante 1, Herbert Budka 2, Sebastian Brandner 1, and John Collinge 1

1 MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
2 Institute of Neurology, Medical University Vienna, Wien, Austria

* To whom correspondence should be addressed.
Jonathan D. F. Wadsworth, E-mail: j.collinge{at}prion.ucl.ac.uk


  Abstract

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 (PrPSc) 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 PrPSc in P102L individuals. PrPSc 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.

Keywords: Creutzfeldt-Jakob disease; Gerstmann-Sträussler-Scheinker disease; prion protein; prion disease.
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