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J. Biol. Chem., Vol. 278, Issue 51, 51770-51778, December 19, 2003

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Lithostathine Quadruple-helical Filaments Form Proteinase K-resistant Deposits in Creutzfeldt-Jakob Disease^*

Emmanuelle Laurine, Catherine Grégoire, Marcus Fändrich, Sabine Engemann¶, Stéphane Marchal||, Laurent Thion**, Michel Mohr, Bernard Monsarrat**, Bernard Michel, Christopher M. Dobson¶¶, Erich Wanker¶, Monique Érard**, and Jean-Michel Verdier||||

From the École Pratique des Hautes Études, Montpellier 34095 cedex 05, France, Institut für Molekulare Biotechnologie, Jena D-07708, Germany, ^¶Neuroproteomics Section, Max-Delbrueck Center for Molecular Medicine, Berlin D-13125, Germany, ^||INSERM U128, Montpellier 34095 cedex 05, France, ^**Institut de Pharmacologie et de Biologie Structurale, Toulouse 31077 cedex 04, France, Service d'Anatomie Pathologique Générale, Hôpital de Hautepierre, Strasbourg 67100, France, Unité de Neurogériatrie, Hôpital Sainte-Marguerite, Marseille 13385 cedex 05, France, and ^¶¶Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom

Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6']bibenzothiazolyl-2,2'-diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.

Received for publication, June 25, 2003 , and in revised form, September 16, 2003.

^* This work was supported in part by the Groupe d'Intérêt Scientifique (GIS) "Infections à prions" (F37 and A43 (to C. G.)), by Groupe de Recherche sur la Maladie d'Alzheimer (to E. L.), by France Alzheimer, by a program grant from the Wellcome Trust (to C. M. D.), and by the Deutsche Forschungsgemeinschaft (to M. F.). 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.

^|||| To whom correspondence should be addressed: Université Montpellier II, Place Eugène Bataillon, EPHE, CC94, Montpellier 34095 cedex 05, France. Tel./Fax: 33-4-67-14-32-91; E-mail: verdier{at}univ-montp2.fr.

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