Atypical Prion Protein Conformation in Familial Prion Disease with PRNP P105T Mutation

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.


Abstract

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.


Keywords

familial prion disease, misfolded protein assay, prion.

Corresponding authors:

Adriano Aguzzi, MD PHD, Institute of

Neuropathology, University Hospital of Zurich,

Schmelzbergstrasse 12, Zurich CH-8091,

Switzerland (E-mail: adriano.aguzzi@usz.ch);

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:

mpolymen@ucsd.edu)

Received 2 June 2010; accepted 2 August

2010.

* These authors contributed equally to this

work.

doi:10.1111/j.1750-3639.2010.00439.x

http://www.pathol.uzh.ch/publications/2010/Polymenidou_BrainPath_2010.pdf



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


http://prionopathy.blogspot.com/2010/11/variably-protease-sensitive-prionopathy.html



http://sporadicffi.blogspot.com/



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