Weizmann Researchers Find Evidence That Links a Molecular Mechanism to Huntington's Disease


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Weizmann researchers have found evidence that an enzyme called transglutaminase (TGase) may be the "smoking gun" behind the deadly disease Huntington's disease (HD). Their study is reported in the June 22 issue of the Proceedings of the National Academy of Sciences.

TGase occurs naturally throughout the body, and is catalyst for processes associated with healing, such as skin formation and wound healing. But a 1993 study by Prof. Howard Green (now of the Department of Cell Biology, Harvard Medical School, Boston) suggested that because of their polymerizing properties, they might also act as a catalyst for aggregating a protein associated with HD called Huntingtin (htt). Prof. Lawrence Steinman (then of the Weizmann Institute's Department of Immunology, now of Stanford University's Department of Neurological Science), together with Weizmann graduate student, Marcela Karpuj and a team of researchers in the United States, have now provided clear evidence of elevated TGase activity in the postmortem brains of HD patients.

Patients who suffer from HD have aggregations-visible clumps-of htt in their brains, but not in other tissues.This makes aggregated htt a good pathological indicator for the disease. Steinman, Karpuj, and the other members of the team decided to look for a correlation between clumps of htt and TGase among patients with HD.
They found elevated TGase activity in the cortex, the cerebellum, and the brain nuclei-all areas in the brain where htt gets concentrated into nuclear inclusions. Correspondingly, they found reduced TGase activity in lymphoblastoid cells-areas where htt does not aggregate. TGase, therefore, appears to be the "smoking gun" that leads to the formation of nuclear inclusions (htt aggregations) in HD patients.

Their research is unique, because for the first time, researchers were able to report on TGase activity in the brains of HD patients rather than in guinea pigs or rats.They compared five postmortem brains of HD patients of different ages to those of a control group of non-HD patients between the ages of 30 and 80. "Karpuj was determined to measure transglutaminase activity in authentic brain tissue from HD patients at the site where the aggregates occurred in the brain nuclei," says Steinman, Karpuj's mentor."No one had attempted such measurements before, not even Prof. Green, who first had proposed that transglutaminase was the culprit back in 1993."

Although Steinman doubted that such measurements could be done on real brain specimens, Karpuj's persistence and her ability to modify techniques to measure TGase activity in human brain tissue were soon rewarded.

In fact, Steinman and Karpuj's novel findings appear to counter earlier, highly publicized findings, conducted in vitro, which linked the disease to the formation of amyloids (extracellular fibrillar protein deposits) in the brain. According to Steinman, the current research found no evidence of amyloids in nuclear inclusions in the HD brains, and no evidence of the much-publicized protein zipper.

Karpuj had argued that TGase would not aggregate the HD protein into orderly  sheets but rather into a very chaotic clump. Together with Hideki Garren, a post-doc in the Steinman laboratory at Stanford University, Karpuj tested the ability of TGase to aggregate htt in vitro, where they found that the clumps were indeed very chaotic.

When neuropathologists Profs. Donald Price, Chief of Neuropathology at Johns Hopkins School of Medicine, Baltimore, and Mark Becher, Chief of Neuropathology at the University of New Mexico Health Sciences Center, Albuquerque examined the HD brains, they saw the identical pattern, confirming Karpuj's findings.

Huntington's disease is an inherited, neurological, degenerative disease for which there is currently no medical treatment. The disease, which usually appears in young or middle-age adults, causes severe, involuntary muscle twitches. It progresses until it affects the entire body, leading to mental deterioration and death. 
The latest research results may eventually lead to the development of new treatments for patients suffering from HD and similar diseases, by inhibiting TGase activity in their brains.

Yeda Research and Development Co Ltd., which deals with the commercialization of Weizmann Institute research, has filed for worldwide patents on a method for treating HD and other neurodegenerative conditions using TGase inhibitors.

Funding for this study was provided by a grant from the U.S. National Institutes of Health, the Hereditary Disease Foundation, the Abraham and Sonia Rochlin Foundation (Reno, NV), the Wolfson Foundation (United Kingdom), Neurocrine Biosciences, Inc. (San Diego, CA), and the Weizmann Institute of Science. The research team also included Hilda Slunt of Johns Hopkins School of Medicine, Baltimore, MD, and Prof. James Gusella, Chief of the Neurogenetics Laboratory, Harvard Medical School, Cambridge, MA.

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