A compound that inhibits enzymes that act as stop signs for genes counteracts the movement disorders brought on by Huntington’s disease, a mouse study suggests.
In this hereditary disease, a genetic mutation results in oversized versions of the so-called huntingtin protein, portions of which stack up in the nuclei of brain cells. Patients develop impairments of thought, movement, and emotions for which there is no treatment or cure.
The mutant version of the huntingtin protein inhibits the action of indispensable enzymes, called acetyltransferases, in brain cells (SN: 4/28/01, p. 271: Huntington’s protein may be kidnapper). Responding to chemical signals, acetyltransferases normally work with other cellular chemicals to switch on genes as needed. Counterpart enzymes, called deacetyltransferases, reverse the process and shut off the genes once they’ve done their job.
As chunks of mutated huntingtin proteins aggregate in cell nuclei and bind to acetyltransferases, they jam the gene-regulatory system, says Joan S. Steffan of the University of California, Irvine. Whether this aggregation directly causes Huntington’s disease or is part of a more complex process is an open question, she notes.
One potential approach to keeping Huntington’s disease in check is to leave already-activated genes turned on longer by incapacitating the deacetyltransferases that put the brakes on them. Earlier work in fruit flies suggested that inhibitors of one such enzyme, called histone deacetyltransferase (HDAC), improved survival and lessened brain-cell loss (SN: 11/24/01, p. 332: Cancer drugs may thwart Huntington’s).
In the new study, Steffan and her U.S. and British colleagues added an HDAC inhibitor called suberoylanilide hydroxamic acid to the drinking water of young mice genetically engineered to make mutated huntingtin protein. These mice showed significantly less movement loss during the 8-week study than similar mice getting plain water did, the researchers report in the Feb. 18 Proceedings of the National Academy of Sciences.
James M. Olson of the Fred Hutchinson Cancer Research Center in Seattle says he has been surprised that an HDAC inhibitor could work without damaging cells. After all, he explains, the powerful chemical alters a fundamental gene activity.
Mark W. Becher of the University of New Mexico in Albuquerque rates the mice’s retention of movement as encouraging. This result suggests that suberoylanilide hydroxamic acid is targeting a deficit in the brain-muscle connection, which ideally would translate into treatments that improve the quality of life for Huntington’s patients, he says. The HDAC inhibitor might be paired with experimental treatments that reduce protein aggregation in cell nuclei, he says.
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