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J. Biol. Chem., Vol. 281, Issue 46, 34848-34858, November 17, 2006
 

Insoluble Aggregates and Protease-resistant Conformers of Prion Protein in Uninfected Human Brains^*

Jue Yuan, Xiangzhu Xiao, John McGeehan¹, Zhiqian Dong, Ignazio Cali, Hisashi Fujioka, Qingzhong Kong, Geoff Kneale, Pierluigi Gambetti, and Wen-Quan Zou²

From the Department of Pathology and National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio 44106 and the Biophysics Laboratories, Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, Portsmouth PO1 2DT, United Kingdom

Aggregated prion protein (PrP^Sc), which is detergent-insoluble and partially proteinase K (PK)-resistant, constitutes the major component of infectious prions that cause a group of transmissible spongiform encephalopathies in animals and humans. PrP^Sc derives from a detergent-soluble and PK-sensitive cellular prion protein (PrP^C) through an -helix to -sheet transition. This transition confers on the PrP^Sc molecule unique physicochemical and biological properties, including insolubility in nondenaturing detergents, an enhanced tendency to form aggregates, resistance to PK digestion, and infectivity, which together are regarded as the basis for distinguishing PrP^Sc from PrP^C. Here we demonstrate, using sedimentation and size exclusion chromatography, that small amounts of detergent-insoluble PrP aggregates are present in uninfected human brains. Moreover, PK-resistant PrP core fragments are detectable following PK treatment. This is the first study that provides experimental evidence supporting the hypothesis that there might be silent prions lying dormant in normal human brains.

 

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Received for publication, March 9, 2006 , and in revised form, September 18, 2006.

^* This work was supported by a Career Developmental Award from STERIS Co. (to W. Q. Z.) and National Institutes of Health Grants AG-14359 and AG08702, the Center for Disease Control and Prevention Contract UR8/CCU515004, and the Britton Fund (to P. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: EMBL, 6 Rue Jules Horowitz, 38042 Grenoble, France.

² To whom correspondence should be addressed. Tel.: 216-368-8993; Fax: 216-368-2546; E-mail: wenquan.zou@case.edu .

http://www.jbc.org/cgi/content/abstract/281/46/34848?ct