GENE ANOMALY ISOLATED WHICH IS CAUSE OF DEMENTIA

INDIANAPOLIS—Researchers have long known that the tau protein plays a role in various dementias, including Alzheimer’s disease. But now a select group of scientists have isolated a mutation in the gene for tau which is the cause of a type of dementia.

Researchers at Indiana University School of Medicine and the Medical Research Council of Great Britain will publish their findings in an upcoming issue of the Proceedings of the National Academy of Sciences. Their research also will be featured in an article in the June 5 issue of the magazine Science, the publication of the American Association for the Advancement of Science.

The findings have major importance for frontotemporal dementias and may also have implications for Alzheimer’s disease. No one knows for sure, but it is believed that frontotemporal dementias account for 4 percent to 10 percent of all dementias.

Many Alzheimer’s disease researchers had all but abandoned the idea that the tau protein played an integral role in some dementias, looking instead at a protein called Beta amyloid. Genetic research in the labs of Bernardino Ghetti, M.D., of Indiana University, and Maria Grazia Spillantini, Ph.D., of the Medical Research Council in Cambridge, England, continued into the causes of dementia. Drs. Ghetti and Spillantini, along with their colleagues Martin Farlow, M.D., and Jill R. Murrell, Ph.D., of Indiana University, and Michael Goedert, M.D., Ph.D., and Aaron Klug, Ph.D., of the Medical Research Council, then isolated the tau anomaly.

In 1993, Dr. Farlow first became acquainted with the family whose disease led to the discovery of the tau anomaly. The researchers studied 11 affected family members in three generations of the family. This family’s disease is unique because it is exclusively tau related, unlike other dementias which could have multiple causes.

In 1997, the Indiana University and Medical Research Council scientists published their findings which identified the family’s disease as a hereditary dementia, naming it familial multiple system tauopathy with presenile dementia (MSTD). Continued research with the members of the family led to the identification of the anomaly in the tau gene and the isolation of its mutations, the findings which are now being released.

“Several varieties or forms of the tau protein are normally found in the brain. What we discovered is a difference in the amounts of some forms of the tau protein produced in patients with MSTD,” said Dr. Ghetti. “Although we believe the actual composition of the protein is the same in affected and non-affected individuals, the mutation in the tau gene causes an overabundance of some forms of the tau protein.”

Tau protein is a key part of the structure of the axons, which link cells in the brain. The axons, in effect, act like telephone lines connecting various phones or, in this case, cells. In the tauopathy patient, tau protein no longer supports the axons, in effect destablizing the line so it can no longer carry signals. When the system is no longer adequately linked, phone service is disrupted or rather, brain function is diminished. This may cause various symptoms in patients such as imbalance, memory loss, verbal dysfunction, depression, obsessive or bizarre behavior, and ultimately dementia.

Another breakdown in the system is caused by an abnormal amount of the tau protein concentrating inside the cells, which causes cell death. The abnormal deposits of the tau protein in the cells form what researchers call tau filaments.

It is possible that the mechanisms that cause MSTD and the other related frontotemporal dementias may also contribute to the development of Alzheimer’s disease. Researchers say that by isolating the tau gene anomaly, scientists are one step closer to developing drugs which can act on the contributing factors of frontotemporal dementias.

Funding for the research was provided through grants from the National Institute on Aging and the National Institute of Neurological Diseases and Stroke, both part of the National Institutes of Health, along with the United Kingdom Medical Research Council, the Royal Society of London and the Metropolitan Life Foundation.

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Contact: Mary Hardin
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mhardin@iupui.edu

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