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Gene expression in Huntington's disease
By Marina Chicurel

Fig. 1
Scanned image of gene chip from an Affymetrix Mu6500 array set hybridized to complementary RNA probe derived from mouse striatal RNA.*

The genes involved in the cascade of brain damage that afflicts patients with Huntington's disease are coming into focus and providing new perspectives on therapy development.

Until recently, researchers working on Huntington's disease—an incurable neurological disorder that slowly mangles its victims' ability to control their movements—faced the infeasible task of reconstructing a war from snapshots of the front lines taken years after the major battles were fought. Having access to brain tissues from patients who had suffered from the disease for years, researchers found dead neurons and shrunken brain regions, but could infer precious little about how or why these defects developed.

Powerful new tools, however, are now allowing scientists to dissect the progression of Huntington's disease. A multi-institutional team led by James Olson, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, monitored the genes of mice carrying a mutated copy of the Huntington's gene, and pinpointed changes that occur just as the first symptoms start to emerge. "The mouse models provide a window into the early stages of the disease," says Ruth Luthi-Carter of the Massachusetts General Hospital in Boston.

Fig. 2 N10 in situ hybridization
R6/2 mice show decreased expression of transcription factor N10 mRNA. Positive signal = dark labeling. Left panels campare wild-type and transgenic mice at six weeks of age. Right panels show a persistent decrease in N10 mRNA in R6/2 brains late in the disease process (at 12 weeks of age).**

The team used gene chips, which reveal the activities of thousands of genes at once, to monitor approximately 6,000 genes in the striatum, a brain region particularly damaged by Huntington's. They found that a small subset of genes, less than two percent of the total, was affected by the disease. Most strikingly, the activities of genes involved in the striatum's signaling system seemed to be blunted. Although previous studies had shown that signaling systems, including neurotransmitter systems that relay messages between nerve cells, are disrupted by Huntington's disease, the study provides new molecular handles to guide the development of therapy.

"This is a nice example of taking the analysis of mouse models to the modern next step," says Harry Orr of the University of Minnesota in Minneapolis. "It points the way for future studies." And, adds Marie Françoise Chesselet of the University of California, Los Angeles, "Although it can look like a fishing expedition, this analysis turned out to have an immediate consequence for thinking how to go about treating this disease."

The study points to several signaling molecules that could be targeted in future treatments. For example, Olson and his colleagues realized that one fifth of the genes altered in Huntington's seem to be regulated by retinoids, molecules that modulate the development and maturation of neurons. In addition, the expression of a retinoid receptor, RXRg, is decreased in the sick mice. Developing strategies to compensate for this disrupted pathway may someday lead to new therapies.

But much remains to be done. "We ultimately want to understand what starts the disease," says Chesselet. To do that, researchers will have to focus on even earlier stages. Although some of the mice in this study were just beginning to show symptoms, they had already gone through many neurological alterations, so many of the newfound gene changes probably reflect secondary events, including the brain's attempts at compensating for earlier damage. "Ideally, we'd want to have a detailed time course of the disease," says Chesselet.

It will also be important to determine which of the changes are critical. "These will be difficult experiments," Orr says. "That's where the creativity and ingenuity are going to come in."

*Fig. 1 created by Ruth Luthi-Carter, Andy Strand, and James Olson.
**Fig. 2 created by Ruth Luthi-Carter and Boris Spektor.

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Luthi-Carter, R. et al. Decreased expression of striatal signaling genes in a mouse model of Huntington's disease. Hum Mol Genet 9, 1259-1271 (May 15, 2000).

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