Johns Hopkins Researchers Slow Progression of Huntington's Disease in Mouse Models
Working with genetically engineered mice, Johns Hopkins researchers have discovered that a gene (SIRT1) linked to slowing the aging process in cells also appears to dramatically delay the onset of Huntington’s disease (HD) and slow the progression of the relentless neurodegenerative disorder.
HD in humans is a rare, fatal disorder caused by a mutation in a single gene and marked by progressive brain damage. Symptoms, which typically first appear in midlife, include jerky twitch-like movements, coordination troubles, psychiatric disorders and dementia. Although the gene responsible for HD was identified in 1993, much is still unknown about the biology of the disease. There is no cure, and there are no effective treatments.
In studying two separate mouse models of HD, the Johns Hopkins team found that mice bred with Huntington’s disease and a greater than usual amount of the enzyme whose blueprint is carried by the SIRT1 gene had improved motor function and reduced brain atrophy. Other studies have suggested SIRT1 has anti-aging and anti-inflammatory properties that scientists are only beginning to understand.
“Our research opens new avenues in the fight against HD, suggesting that if we target SIRT1, we may be able to find drugs that offer help to patients for whom we currently have really nothing that works,” says Wenzhen Duan, M.D., Ph.D., an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
A report on the findings by Duan and her international team will be published online in Nature Medicine.
In previous work with HD mice, Duan and her colleagues found that calorie restriction (reducing calories by about 30 percent through alternate day feeding) slowed the disease progression and extended lifespan. SIRT1 activity was associated with the increased longevity, owing to its ability to reduce hyperglycemia and improved glucose tolerance while mitigating metabolic problems in the animals. That experience with SIRT1 and HD mice led Duan to look more closely at the possible connection between the enzyme and the mutation in the huntingtin gene (HTT), which causes HD. The mutation results in the production of an abnormal and toxic version of the huntingtin protein.
Although HTT is expressed all over the body, the disease does its characteristic damage in the part of the brain that controls movement, most notably in the medium spiny neurons. Duan and her colleagues have determined that SIRT1 preserves the function of these medium spiny neurons and that extra SIRT1 seems to prevent a decline in levels of brain-derived neurotrophic factor, or BDNF, which acts as nutrition for brain cells. People with HD tend to have low levels of BDNF.
People with a family history of HD can be tested for the gene that causes it long before the onset of symptoms, but many choose to not be tested, Duan says, because nothing can be done to prevent or treat the symptoms.
The research was supported by the Hereditary Disease Foundation, CHDI, the National Institutes of Health, and the National Institute of Aging Intramural Research Program.
Other Johns Hopkins researchers involved in the study include Mali Jiang, M.D., Ph.D.; Jiawei Wang, M.D.; Jinrong Fu, Ph.D.; Lan Xiang, Ph.D.; Qi Peng; Zhipeng Hou; Nicolas Arbez, Ph.D.; Shanshan Zhu, Ph.D.; Katherine Sommers; Jennifer Qian; Jiangyang Zhang, Ph.D; Susumu Mori, Ph.D.; Kellie L.K. Tamashiro, Ph.D.; Susan Aja, Ph.D.; Timothy H. Moran, Ph.D.; and Christopher A. Ross, M.D., Ph.D.
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