ZFIN ID: ZDB-PUB-061229-4
Identification of anti-prion compounds as efficient inhibitors of polyglutamine protein aggregation in a zebrafish model
Schiffer, N.W., Broadley, S.A., Hirschberger, T., Tavan, P., Kretzschmar, H.A.,Giese, A., Haass, C., Hartl, U.F., and Schmid, B.
Date: 2007
Source: The Journal of biological chemistry   282(12): 9195-9203 (Journal)
Registered Authors: Haass, Christian, Schmid, Bettina
Keywords: none
MeSH Terms:
  • Animals
  • Apoptosis*
  • Green Fluorescent Proteins/chemistry
  • HSP40 Heat-Shock Proteins/chemistry
  • HSP70 Heat-Shock Proteins/chemistry
  • Models, Chemical
  • Models, Molecular
  • Mutation*
  • Peptides/chemistry*
  • Peptides/metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Subcellular Fractions
  • Thermodynamics
  • Zebrafish
PubMed: 17170113 Full text @ J. Biol. Chem.
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.