Everyone agrees: from plaques to tangles, Alzheimer's to Parkinson's, insoluble protein bodies are associated with neurodegeneration. This begs the obvious question: If you were to prevent the proteins from aggregating could you cure the disease? The answer seems to be yes, at least in the case of Huntington's disease.

Together with David Housman at MIT, Leslie Thompson, University of California, Irvine, has developed peptide suppressors that inhibit the aggregation of polyglutamine (polyQ)-expanded huntingtin, the protein that causes Huntington's disease. These peptides also protected Drosophila against the lethal effects of polyQ proteins. Thompson reported her findings in the 25 March Nature Genetics online.

The peptides were engineered to have polyQ tracts of their own, separated by an α-helical spacer. The rationale was to design a molecule that would bind tightly to polyQ expanded proteins, yet prevent them from aggregating. The best suppressor increased from 1 to 50 percent the chances of Drosophila surviving expression of a polyQ108-containing protein. In addition, polyQ-induced degeneration of photoreceptor neurons, which is easily measured in flies, was substantially improved when suppressors were co-expressed with the expanded protein.

"This was a very nicely carried-out study," said James Burke, Duke University, who has discovered similar suppressors using phage display screening (Nagai et al 2000). "The authors looked at a number of different levels of organization. The real value is that it demonstrates that disrupting polyglutamine expansion aggregation in an animal model results in normalization."—Tom Fagan


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External Citations

  1. Nagai et al 2000

Further Reading

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Primary Papers

  1. . A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nat Genet. 2002 Mar 25; PubMed.