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

MPS-Authors

Heiser,  Volker
Max Planck Society;

Engemann,  Sabine
Max Planck Society;

Bröcker,  Wolfgang
Max Planck Society;

/persons/resource/persons50140

Dunkel,  Ilona
Computational Epigenetics (Ho-Ryun Chung), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50107

Boeddrich,  Annett
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

Waelter,  Stephanie
Max Planck Society;

Nordhoff,  Eddi
Max Planck Society;

Lurz,  Rudi
Max Planck Society;

Schugardt,  Nancy
Max Planck Society;

Rautenberg,  Susanne
Max Planck Society;

/persons/resource/persons50409

Lehrach,  Hans
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

Wanker,  Erich E.
Max Planck Society;

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Citation

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.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0010-8BBA-8
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.