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Neurodegenerative disorders

Netting the aggregate

Nature Reviews Neuroscience volume 3, page 763 (2002)Cite this article

HD, and the formation of aggregates, results when a threshold number of glutamine residues (>37), which are encoded in exon 1 of the huntingtin gene, are present in the huntingtin protein. The screening process that the authors have developed relies on the fact that aggregated huntingtin is retained by cellulose-acetate membranes, whereas unaggregated huntingtin is not. After incubating a polyglutamine-containing HD exon 1 fusion protein with potential inhibitor compounds in a 384-well format, the reaction mixtures were filtered through cellulose acetate and captured aggregates were revealed by immunoblotting. Testing a Merck compound library of ∼184,000 molecules exposed five groups of structurally similar compounds that reduced the level of aggregation.

The authors reveal the identity of one of the compound groups, which are benzothiazoles that are closely related to Riluzole, a compound that is already used for the treatment of amyotrophic lateral sclerosis. The most potent in vitro inhibitors were, however, shown to be toxic in a cell-based assay of aggregation inhibition, highlighting the difficulty in translating in vitro screening results into therapy.

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ORIGINAL RESEARCH PAPER

  1. Heiser, V. et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc. Natl Acad. Sci. USA 28 August 2002 (doi:10.1073/pnas.182426599)

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  1. Editor, Nature Reviews Drug Discovery,

    Adam Smith

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  1. Adam Smith
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Smith, A. Netting the aggregate. Nat Rev Neurosci 3, 763 (2002). https://doi.org/10.1038/nrn946

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