Might a simple sugar derail Huntington's?

People with Huntington's disease gradually lose neurons in their brains as defective protein molecules clump together inside those cells. Scientists in Japan now report that a simple sugar called trehalose can impede this protein aggregation in test-tube and animal experiments.

Trehalose joins a growing list of potential Huntington's disease fighters (SN: 2/15/03, p. 10;11/24/01, p. 332). These include proteins that prevent enzymes from triggering cell death, antibiotics, and other compounds that inhibit protein aggregation.

In an upcoming Nature Medicine, the Japanese researchers demonstrate that among mice with a version of Huntington's disease, those fed trehalose outlive their littermates and better fend off the disease.

Roughly 30,000 people in the United States have Huntington's disease, a condition marked by a loss of coordination, slurred speech, swallowing difficulties, and other problems. The illness, which usually appears in middle age, arises from an inherited genetic mutation that creates an overabundance of the amino acid glutamine in the protein called huntingtin. The excess glutamines cause unnatural folds that expose sticky portions of the protein, probably triggering the clumping inside neurons, says neuroscientist Nobuyuki Nukina of the RIKEN Brain Science Institute in Wako. Many scientists hold that this protein aggregation causes the disease.

In the new study, Nukina and his colleagues screened more than 200 compounds for their capacity to inhibit aggregation of proteins containing extra glutamines. These test-tube experiments revealed that trehalose--a sugar naturally made by organisms including yeast, bacteria, and insects--inhibits the aggregation. The sugar probably binds to some exposed portion of a glutamine-loaded protein, Nukina says. Further testing in lab dishes containing neurons from mice genetically engineered to make a portion of the human mutant huntingtin protein showed that trehalose inhibits the protein clustering.

Nukina and his colleagues then turned to live mice. In a series of tests, the scientists found that when such animals received trehalose in their drinking water, they had fewer protein aggregations in their brain cells, less brain-cell death, and better scores on coordination tests than did similar mice not getting trehalose. Survival benefits, however, were modest. On average, the trehalose-treated mice lived 108 days versus 97 days for the untreated mice. Another sugar, glucose, showed no effects.

"This is a nice, elegant study," says Robert M. Friedlander, a neurosurgeon at Harvard Medical School and Brigham and Women's Hospital in Boston. He notes that the work starts at a basic level--a hunt for compounds that bind to glutamine-loaded proteins--then tests whether the selected substance thwarts the aggregation of proteins in cells. "Remarkably, trehalose seems to work in a mouse model too," he says.

The sugar is already added to foods as a sweetener. The researchers are now considering a test of the substance as an oral drug in Huntington's patients.

Friedlander says that Huntington's disease might ultimately be treated "with a cocktail of medications ... each with a different mechanism of action."

Trehalose might have other uses, says Christopher Ross, a neuroscientist at Johns Hopkins Medical Institutions in Baltimore. "It might be relevant to other neurodegenerative diseases that involve protein aggregations," such as Alzheimer's and Parkinson's diseases, he notes.