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J. Biol. Chem., Vol. 281, Issue 19, 13559-13565, May 12, 2006

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The Interaction between Cytoplasmic Prion Protein and the Hydrophobic Lipid Core of Membrane Correlates with Neurotoxicity^*

Xinhe Wang, Fei Wang, Linnea Arterburn, Robert Wollmann, and Jiyan Ma¹

From the Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210 and the Department of Pathology, University of Chicago, Chicago, Illinois 60637

Prion protein (PrP), normally a cell surface protein, has been detected in the cytosol of a subset of neurons. The appearance of PrP in the cytosol could result from either retro-translocation of misfolded PrP from the endoplasmic reticulum (ER) or impaired import of PrP into the ER. Transgenic mice expressing cytoplasmic PrP (cyPrP) developed neurodegeneration in cerebellar granular neurons, although no detectable pathology was observed in other brain regions. In order to understand why granular neurons in the cerebellum were most susceptible to cyPrP-induced degeneration, we investigated the subcellular localization of cyPrP. Interestingly, we found that cyPrP is membrane-bound. In transfected cells, it binds to the ER and plasma/endocytic vesicular membranes. In transgenic mice, it is associated with synaptic and microsomal membranes. Furthermore, the cerebellar neurodegeneration in transgenic mice correlates with the interaction between cyPrP and the hydrophobic lipid core of the membrane but not with either the aggregation status or the dosage of cyPrP. These results suggest that lipid membrane perturbation could be a cellular mechanism for cyPrP-induced neurotoxicity and explain the seemingly conflicting results concerning cyPrP.

Received for publication, November 16, 2005 , and in revised form, March 10, 2006.

^* This work was supported in part by a new scholar award from the Ellison Medical Foundation (to J. M.) and a Pfizer/AFAR Innovations in Aging research grant (to J. M.). 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: Dept. of Molecular and Cellular Biochemistry, Ohio State University, 1645 Neil Ave., Columbus, OH 43210. Tel.: 614-688-0408; Fax: 614-292-4118; E-mail: ma.131{at}osu.edu.

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