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Leslie Thompson hunts toxic proteins in search for treatment of deadly brain disease

AAAS Fellow Leslie Thompson is using skin cells to create brain cells that have the abnormal protein that causes Huntington's Disease, and she is testing treatments with those cells. (Photo: Rebecca Fairley Raney)

Some scientists get the chance to identify a gene that causes a deadly disease. Others spend their careers testing ways to treat those diseases. But few, in a single career, get the chance to do both.

In the past 20 years, Leslie Thompson has done both. What's more, she has done it after taking time away from science early in her career to raise children.

During her post-doctoral work in 1993 at the University of California at Irvine, the AAAS fellow worked with the group that identified the unstable DNA segment that causes Huntington's Disease, a degenerative disorder that destroys brain cells and kills people in the prime of life. In recent years, Thompson's lab has been the first to discover how toxic proteins build up in diseased brain cells.

The symptoms of Huntington's start when people experience personality changes and have trouble getting through the day; they can no longer both put dinner on the stove and do the laundry. They become aggressive or paranoid. As the disease progresses, they can lose control of speech or movement.

Right now, there is no treatment for Huntington's Disease. If you have one parent who carries the mutation that causes the disease, you have a 50-50 chance of getting it. And if you have the mutation, you will get the disease. It afflicts at least 1 in 10,000 people.

To study how the mutation works, Thompson, whose doctorate is in biological chemistry and genetics, has developed models of the disease in fruit flies and mice. In the mice, she injected normal neural stem cells to see if those cells would confer benefits to the diseased neurons. They did. The normal stem cells protected the neurons.

In other research at the university's Sue & Bill Gross Stem Cell Research Center, she has been the first to use skin cells to create brain cells that have the abnormal protein that causes the disease, and she is testing treatments with those cells.

On the quest for a cure

Thompson's models of the disease are unique, and she has shared them freely with other research groups.

"She's been the key person to develop these cells," said Anne B. Young, distinguished Julieanne Dorn professor of neurology at Harvard Medical School. "Her own laboratory has dealt with questions that ask about regulatory functions of the cell."

Changes in the production of a protein called huntingtin alter the function of the cells. The protein is named after George Huntington, the doctor who first described characteristics of the disease in the 19th century.

The genetic mutation that causes the disease involves a segment of DNA that can repeat within a gene from 36 to 120 times. In people without the mutation, that segment repeats from 10 to 35 times. The more the segment repeats, the worse the symptoms of the disease. In neurons, the abnormal production of the protein causes just about everything to go wrong, Thompson said.

Either finding ways to disrupt those modifications, or enhancing the normal functioning of the protein, could provide ways to treat the disease, which kills adults 15 to 20 years after onset.

Balancing family and a research career

In pursuing a career that takes her into the clinic and the lab, Thompson has returned to an ambition that was thwarted when she was younger.

Before she was a scientist, Thompson wanted to be a doctor. As a young medical student, she got married and had a baby. After the baby was born, she stepped away from medical school to take time for her family.

Later, while her husband attended medical school at UCI, she entered graduate school there to study genetics. During an era when benefits like maternity leave were generally not available to graduate students, Thompson's mentors made a point to extend those benefits to her.

When Thompson had her second baby, her graduate mentor, Lee Henn, gave her maternity leave. Ultimately, Thompson took three years off. Henn, a professor of biological chemistry, not only let her return to the program after the time off, but also offered flexible hours.

In the course of studying Huntington's Disease, Thompson has been in constant contact with patients. With this disease, the research and therapeutic communities are tightly linked. It's not unusual for patients to ask questions at science meetings.

The recent breakthroughs in understanding Huntington's Disease are encouraging, but Thompson describes the prospects for finding a treatment with the caution that comes from routinely looking patients in the eye.

"Every time we say it's five to 10 years down the road," she said, \ten years passes and the patient families say, 'You said 10 years.'

"I do have huge hope that in the near future, there will at least be treatments that change the course of the disease. Right now, there's nothing."

Representative Image Caption
AAAS Fellow Leslie Thompson is using skin cells to create brain cells that have the abnormal protein that causes Huntington's Disease, and she is testing treatments with those cells. (Photo: Rebecca Fairley Raney)
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