RESEARCH A R T I C L E bpa_439 1..6
Atypical Prion Protein Conformation in Familial Prion Disease with PRNP P105T Mutation
Magdalini Polymenidou1,2,*; Stefan Prokop1,3,*; Hans H. Jung4; Ekkehard Hewer1; David Peretz5,6;
Rita Moos1; Markus Tolnay1,7; Adriano Aguzzi1
4 Department of Neurology, 1 Institute of Neuropathology, University Hospital Zurich and 7 Basel, Switzerland.
5 Novartis Vaccines and Diagnostics, Emeryville, Calif.
2 Current address: Department of Cellular and Molecular Medicine, University of California at San Diego, Calif.
3 Current address: Department of Neuropathology, Charité—Universitätsmedizin Berlin, Germany.
6 Current address: Tethys Bioscience, Emeryville, Calif.
Protease-resistant prion protein (PrPSc) is diagnostic of prion disease, yet its detection is
frequently difficult. Here, we describe a patient with a PRNP P105T mutation and typical
familial prion disease. Brain PrPSc was undetectable by conventional Western blotting and
barely detectable after phosphotungstate precipitation, where it displayed an atypical pattern
suggestive of noncanonical conformation. Therefore, we used a novel misfolded protein
assay (MPA) that detects PrP aggregates independently of their protease resistance. The
MPA revealed the presence of aggregated PrP in similar amounts as in typical sporadic
Creutzfeldt-Jakob disease. These findings suggest that measurements of PrP aggregation
with the MPA may be potentially more sensitive than protease-based methodologies.
familial prion disease, misfolded protein assay, prion.
Adriano Aguzzi, MD PHD, Institute of
Neuropathology, University Hospital of Zurich,
Schmelzbergstrasse 12, Zurich CH-8091,
Switzerland (E-mail: email@example.com);
Magdalini Polymenidou, PHD, Department of
Cellular and Molecular Medicine, University of
California, San Diego, 9500 Gilman Drive, La
Jolla, CA 92093-0670, USA (E-mail:
Received 2 June 2010; accepted 2 August
* These authors contributed equally to this
Sunday, November 28, 2010
Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, a synuclein and AB pathology