Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model

doi:10.1074/jbc.M607865200

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Papers In Press, published online ahead of print December 14, 2006
J. Biol. Chem, 10.1074/jbc.M607865200
Submitted on August 16, 2006
Accepted on December 14, 2006

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, Ulrich F. Hartl, and Bettina Schmid

Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, 80336

Corresponding Author: beschmid{at}med.uni-muenchen.de

Several neurodegenerative diseases, including Huntington’s 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 non-vertebrate 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.

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