Muscles may hold clues to fatal brain disease

Unique gene-activity changes can be seen in the muscles of patients with Huntington's disease (HD) according to scientists in the Clinical Research Division. The finding could lead to finely tuned methods to track the progress of this fatal, degenerative brain disorder and ultimately improve doctors' ability to test the effectiveness of new treatments.

Dr. Andy Strand, lead author on the study and a staff scientist in Dr. Jim Olson's lab, has been studying HD since 1998. The findings — published in the July issue of the journal Human Molecular Genetics — may lead to better clinical trials and earlier therapeutic interventions for HD.

HD is an untreatable and deadly inherited disease. Each child of a parent with HD has a 50-50 chance of inheriting the HD gene. HD typically begins in mid-life, between the ages of 30 and 45, which means people may find out they are carriers of the HD gene after they have had children, potentially exposing another generation to the devastation of HD.

The discovery of the HD gene in 1993 resulted in a direct genetic test to make or confirm a diagnosis of HD. But to assess the stage and course of HD, doctors rely on a subjective rating system that uses observation of motor, cognitive, behavioral and functional skills. Strand hopes to find an objective measurement of HD's progression — a biomarker — that will be more sensitive than the rating scale to the first signs and stages of the disease.

"There's a great interest in trying to objectively measure how sick Huntington's patients are," Strand said. "But since it's a very slow disease, it is difficult to quantify its evolution with a neurological exam. These exams are not that sensitive. It is now known that cell loss in the brain begins years before the neurological signs appear. So people are starting to look outside of the brain to try to find ways to measure the illness with biomarkers."

"Ideally, a biomarker would pick up HD symptoms or improvements due to treatment months or years before the clinical rating scale because it's more sensitive," Strand said.

Gene-expression differences

Using mice with a greatly accelerated form of HD, Strand and colleagues found muscle gene-expression differences between HD mice and healthy mice. These differences grew larger as the disease progressed. They also found that there were similar gene-expression differences between muscle biopsies from HD patients and unaffected study participants. Strand has received a grant from the National Institutes of Health to see if these gene changes can be used to measure disease in HD patients.

"Aside from its potential clinical applications, this research may provide insight into the basic mechanisms of neurodegeneration," Strand said.

Studying HD by looking at skeletal muscle is a novel approach. Most HD researchers focus on the brain, since the illness is marked by the deterioration of nerve cells in areas of the brain that control movement. This causes people affected with the disorder to writhe and twist in a constant, uncontrollable dance-like motion. But while the brain is complex and inaccessible, skeletal muscle is simple and well understood.

Muscle cells fuse together into muscle fibers. These fibers are classified as slow-twitch or fast-twitch. Every particular muscle has a characteristic mixture of fibers. Some muscles, like the dark meat in poultry, are adapted for continuous use and consist of more slow twitch fibers. Other muscles, like white meat, consist of more fast twitch fibers and are adapted for short explosive movements. Strand believes that HD triggers a conversion of fast fibers into slow fibers. The trick to understanding how the muscle changes in HD relate to brain disease boils down to deciding if the muscle effect is secondary to the brain changes or due to a problem in the muscle cells themselves.

To distinguish between these possibilities, the Olson lab will generate mice that conditionally express the disease-causing protein in muscle cells. These mice will not have Huntington's disease in the usual sense, but they may develop the same muscle problems that HD mice and patients do.

The High Q Foundation and the Hereditary Disease Foundation funded the study. Co-authors included Hutchinson Center Drs. Aaron Aragaki, Stephen Tapscott, Charles Kooperberg and Jim Olson. Other contributors were Drs. Dennis Shaw and Thomas Bird, University of Washington; Dr. Janice Holton, University College London; Drs. Christopher Turner and Anthony Schapira, Royal Free and University College Medical School, London; and Dr. Sarah Tabrizi, National Hospital for Neurology and Neurosurgery, London.