Although the jury is still out on whether the insoluble deposits that are a characteristic feature of so many neurodegenerative diseases are causative or simply symptomatic, the search to find inhibitors of protein aggregation in such diseases seems to be one of the few possible routes to much-needed therapies. In a paper published in the Proceedings of the National Academy of Sciences, Erich Wanker and colleagues have stepped-up the pace of the search by introducing a simple method for high-throughput screening of compounds that block the self-assembly of poly-glutamine-containing huntingtin aggregates, the pathological hallmark of Huntington's disease (HD).

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.