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  Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay

Heiser, V., Engemann, S., Bröcker, W., Dunkel, I., Boeddrich, A., Waelter, S., et al. (2002). Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington’s disease by using an automated filter retardation assay. Self-Perpetuating Structural States in Biology, Disease, and Genetics, 16400-16406.

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 Creators:
Heiser, Volker1, Author
Engemann, Sabine1, Author
Bröcker, Wolfgang1, Author
Dunkel, Ilona2, Author           
Boeddrich, Annett3, Author           
Waelter, Stephanie1, Author
Nordhoff, Eddi1, Author
Lurz, Rudi1, Author
Schugardt, Nancy1, Author
Rautenberg, Susanne1, Author
Herhaus, Christian, Author
Barnickel, Gerhard, Author
Böttcher, Henning, Author
Lehrach, Hans3, Author           
Wanker, Erich E.1, Author
Affiliations:
1Max Planck Society, ou_persistent13              
2Computational Epigenetics (Ho-Ryun Chung), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479658              
3Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: Preventing the formation of insoluble polyglutamine containing protein aggregates in neurons may represent an attractive therapeutic strategy to ameliorate Huntington's disease (HD). Therefore, the ability to screen for small molecules that suppress the self-assembly of huntingtin would have potential clinical and significant research applications. We have developed an automated filter retardation assay for the rapid identification of chemical compounds that prevent HD exon 1 protein aggregation in vitro. Using this method, a total of 25 benzothiazole derivatives that inhibit huntingtin fibrillogenesis in a dose-dependent manner were discovered from a library of 184,000 small molecules. The results obtained by the filter assay were confirmed by immunoblotting, electron microscopy, and mass spectrometry. Furthermore, cell culture studies revealed that 2-amino-4,7-dimethyl-benzothiazol-6-ol, a chemical compound similar to riluzole, significantly inhibits HD exon 1 aggregation in vivo. These findings may provide the basis for a new therapeutic approach to prevent the accumulation of insoluble protein aggregates in Huntington's disease and related glutamine repeat disorders.

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Language(s): eng - English
 Dates: 2002-08-28
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: eDoc: 24230
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Title: Self-Perpetuating Structural States in Biology, Disease, and Genetics
Source Genre: Issue
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Pages: - Volume / Issue: - Sequence Number: - Start / End Page: 16400 - 16406 Identifier: -

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Title: Proceedings of the National Academy of Sciences
Source Genre: Journal
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Pages: - Volume / Issue: 99 (Suppl. 4) Sequence Number: - Start / End Page: - Identifier: -