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J. Biol. Chem., Vol. 282, Issue 12, 9195-9203, March 23, 2007

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Identification of Anti-prion Compounds as Efficient Inhibitors of Polyglutamine Protein Aggregation in a Zebrafish Model^*

Niclas W. Schiffer, Sarah A. Broadley, Thomas Hirschberger, Paul Tavan, Hans A. Kretzschmar^¶, Armin Giese^¶, Christian Haass^||, F. Ulrich Hartl¹, and Bettina Schmid^||2

From the Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried, Germany, the ^||Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Schillerstrasse 44, D-80336 Munich, Germany, the ^¶Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Feodor Lynen Strasse 23, D-81377 Munich, Germany, and the Chair for BioMolecular Optics, Department of Physics, Ludwig-Maximilians-University, Oettingenstrasse 67, D-80538 Munich, Germany

Several neurodegenerative diseases, including Huntington disease (HD), are associated with aberrant folding and aggregation of polyglutamine (polyQ) expansion proteins. Here we established the zebrafish, Danio rerio, as a vertebrate HD model permitting the screening for chemical suppressors of polyQ aggregation and toxicity. Upon expression in zebrafish embryos, polyQ-expanded fragments of huntingtin (htt) accumulated in large SDS-insoluble inclusions, reproducing a key feature of HD pathology. Real time monitoring of inclusion formation in the living zebrafish indicated that inclusions grow by rapid incorporation of soluble htt species. Expression of mutant htt increased the frequency of embryos with abnormal morphology and the occurrence of apoptosis. Strikingly, apoptotic cells were largely devoid of visible aggregates, suggesting that soluble oligomeric precursors may instead be responsible for toxicity. As in nonvertebrate polyQ disease models, the molecular chaperones, Hsp40 and Hsp70, suppressed both polyQ aggregation and toxicity. Using the newly established zebrafish model, two compounds of the N'-benzylidene-benzohydrazide class directed against mammalian prion proved to be potent inhibitors of polyQ aggregation, consistent with a common structural mechanism of aggregation for prion and polyQ disease proteins.

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

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 596 A9 (to C. H. and B. S.), B6 (to F. U. H.), and B13 (to H. K. and A. G.); the Ernst Jung Foundation and Bundesministerium für Bildung und Forschung Grant 01KO0501 (to T. H., P. T., H. K., and A. G.); the Hereditary Disease Foundation's John J. Wasmuth fellowship (to S. A. B.); and the Hans & Ilse Breuer Foundation (to C. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2, Table S1, and Video S1.

¹ To whom correspondence may be addressed. Tel.: 49-89-8578-2233; Fax: 49-89-8578-2211; E-mail: uhartl{at}biochem.mpg.de.

² To whom correspondence may be addressed. Tel.: 49-89-2180-75453; E-mail: Bettina.Schmid{at}med.uni-muenchen.de.

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