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J. Biol. Chem., Vol. 282, Issue 41, 30022-30028, October 12, 2007

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Cross-sequence Transmission of Sporadic Creutzfeldt-Jakob Disease Creates a New Prion Strain^*

Atsushi Kobayashi, Masahiro Asano, Shirou Mohri, and Tetsuyuki Kitamoto¹

From the Division of CJD Science and Technology, Department of Prion Research, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan and Prion Disease Research Center, National Institute of Animal Health, Tsukuba, Ibaraki 305-0856, Japan

The genotype (methionine or valine) at polymorphic codon 129 of the human prion protein (PrP) gene and the type (type 1 or type 2) of abnormal isoform of PrP (PrP^Sc) are major determinants of the clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). Here we found that the transmission of sCJD prions from a patient with valine homozygosity (129V/V) and type 2 PrP^Sc (sCJD-VV2 prions) to mice expressing human PrP with methionine homozygosity (129M/M) generated unusual PrP^Sc intermediate in size between type 1 and type 2. The intermediate type PrP^Sc was seen in all examined dura mater graft-associated CJD cases with 129M/M and plaque-type PrP deposits (p-dCJD). p-dCJD prions and sCJD-VV2 prions exhibited similar transmissibility and neuropathology, and the identical type of PrP^Sc when inoculated into PrP-humanized mice with 129M/M or 129V/V. These findings suggest that p-dCJD could be caused by cross-sequence transmission of sCJD-VV2 prions.

Received for publication, June 5, 2007 , and in revised form, August 8, 2007.

^* This work was supported by the program for Promotion of Fundamental Studies in Health Sciences of Japanese National Institute of Biomedical Innovation (to S. M. and T. K.), a grant from the Ministry of Health, Labor and Welfare of Japan (to A. K., S. M., and T. K.), and a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to A. K. and T. K.). 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 To whom correspondence should be addressed: Div. of CJD Science and Technology, Dept. of Prion Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Tel.: 81-22-717-8143; Fax: 81-22-717-8148; E-mail: kitamoto{at}mail.tains.tohoku.ac.jp.

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