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J. Biol. Chem., Vol. 283, Issue 35, 24202-24211, August 29, 2008

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Dominant-negative Effects of the N-terminal Half of Prion Protein on Neurotoxicity of Prion Protein-like Protein/Doppel in Mice^*

Daisuke Yoshikawa, Naohiro Yamaguchi, Daisuke Ishibashi, Hitoki Yamanaka, Nobuhiko Okimura, Yoshitaka Yamaguchi^¶, Tsuyoshi Mori^¶, Hironori Miyata^||, Kazuto Shigematsu^**, Shigeru Katamine, and Suehiro Sakaguchi^¶1

From the Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, PRESTO Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, ^¶Division of Molecular Neurobiology, The Institute for Enzyme Research, the University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, ^||Animal Research Center, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu 807-8555, and the ^**Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan

Prion protein-like protein/doppel is neurotoxic, causing ataxia and Purkinje cell degeneration in mice, whereas prion protein antagonizes doppel-induced neurodegeneration. Doppel is homologous to the C-terminal half of prion protein but lacks the amino acid sequences corresponding to the N-terminal half of prion protein. We show here that transgenic mice expressing a fusion protein consisting of the N-terminal half, corresponding to residues 1-124, of prion protein and doppel in neurons failed to develop any neurological signs for up to 730 days in a background devoid of prion protein. In addition, the fusion protein prolonged the onset of ataxia in mice expressing exogenous doppel. These results suggested that the N-terminal part of prion protein has a neuroprotective potential acting both cis and trans on doppel. We also show that prion protein lacking the pre-octapeptide repeat (25-50) or octapeptide repeat (51-90) region alone could not impair the antagonistic function against doppel.

Received for publication, June 2, 2008 , and in revised form, June 16, 2008.

^* This study was supported in part by a Research on Specific Diseases grant from the Ministry of Health, Labor and Welfare, Japan. 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: Division of Molecular Cytology, Institute for Enzyme Research, University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Tel.: 81-88-633-7438; Fax: 81-88-633-7440; E-mail: sakaguch{at}ier.tokushima-u.ac.jp.

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