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

Item Type:Article
Title:Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay
Creators Name:Heiser, V. and Engemann, S. and Broecker, W. and Dunkel, I. and Boeddrich, A. and Waelter, S. and Nordhoff, E. and Lurz, R. and Schugardt, N. and Rautenberg, S. and Herhaus, C. and Barnickel, G. and Boettcher, H. and Lehrach, H. and Wanker, E.E.
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.
Keywords:Benzothiazoles, Cell Line, Electron Microscopy, Exons, Huntington Disease, Indirect Fluorescent Antibody Technique, Nerve Tissue Proteins, Nuclear Proteins, Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry, Peptides, Polyacrylamide Gel Electrophoresis, Thiazoles, Western Blotting
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:99
Number:Suppl 4
Page Range:16400-16406
Date:10 December 2002
Official Publication:https://doi.org/10.1073/pnas.182426599
PubMed:View item in PubMed

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