Drugs developed to fight cancer could also be effective against Huntington’s disease and several related neurodegenerative conditions, according to a new study of flies.
These brain illnesses are known as polygutamine disorders because in each, a mutated gene translates into proteins with an overabundance of the amino acid glutamine (SN: 6/10/95, p. 360). Seeking to explain how different proteins cause these brain disorders, scientists have searched for molecules whose functions might be altered by glutamine-rich proteins.
This molecular hunt is turning up suspects. Earlier this year, for example, a group reported that Htt, the mutant protein encoded by the Huntington’s disease gene, binds to a protein called CBP (SN: 4/28/01, p. 271: Huntington’s protein may be kidnapper).
CBP is an acetyltransferase, an enzyme that directly regulates DNA and the genes it contains. Neuroscientist Leslie M. Thompson of the University of California, Irvine and her colleagues have now found that Htt not only binds to CBP and other acetyltransferases, but also prevents these enzymes from doing their normal gene-orchestrating jobs.
Cancer researchers already have developed drugs that inhibit enzymes that undo the actions of acetyltransferases. Thompson’s group theorized that such drugs, called HDAC inhibitors, also might counteract the gene disruptions caused by glutamine-laden proteins. To test that idea, the researchers fed HDAC inhibitors to fruit flies genetically engineered to make Htt. In the Oct. 18 Nature, the group reports that the treatment delays the brain-cell loss and death that normally strike the mutant insects.
Thomson’s group and several other research teams already have started to test the drugs on mice genetically engineered to have a rodent version of Huntington’s disease. “Depending on what these studies show, there may be human clinical trials,” says Thompson. Citing other groups’ published and unpublished work, she’s optimistic that HDAC inhibitors also will become candidates for treating polyglutamine disorders other than Huntington’s disease.