Weizmann Researchers Link Transglutaminase Activity to Huntington's Disease

Researchers at the Weizmann Institute (Rehovot, Israel) have found evidence that the enzyme transglutaminase (TGase) may be the "smoking gun" behind Huntington's disease (HD). Their study is reported in the June 22 issue of the Proceedings of the National Academy of Sciences, in a paper entitled "Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei."

TGase occurs naturally throughout the body, and is associated with healing processes, such as skin formation and wound healing. But in 1993, Howard Green (now of the Department of Cell Biology at Harvard Medical School, Boston) suggested that because of its polymerizing properties, it might also act as a catalyst for aggregating a protein associated with HD called huntingtin (htt). 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 US, have now demonstrated elevated TGase activity in the postmortem brains of HD patients.

Patients who suffer from HD have aggregations 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 looked for a correlation between clumps of htt and TGase activity in the brains of HD patients. They found elevated TGase activity in the cortex, the cerebellum, and the brain nuclei—all areas in the brain where htt aggregates concentrate into nuclear inclusions. Correspondingly, they found reduced TGase activity in lymphoblastoid cells—areas where htt does not aggregate. TGase, therefore, correlates with htt aggregations in HD patients.

This research is the first report on TGase activity in the brains of HD patients rather than in experimental models. They looked at five postmortem brains of HD patients of different ages 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."

While Steinman doubted that such measurements could be done on real brain specimens, Karpuj was able to modify techniques to allow measurements of TGase activity in human brain tissue.

These findings contradict earlier 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.

Karpuj reasoned that TGase would not aggregate the HD protein into orderly sheets but rather into chaotic clumps. 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, and found that the clumps were indeed chaotic.

Neuropathologists 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), saw identical patterns in HD brains, confirming Karpuj's findings.

Huntington's disease is an inherited, neurological degenerative disease characterized by involuntary muscle twitches that eventually involve the entire body, causing mental deterioration and eventual death. There is currently no medical treatment for the disease. The latest results suggest that TGase inhibitors might provide a treatment for patients suffering from HD and similar diseases.

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

Funding for this study was provided by a grant from the US National Institutes of Health, the Hereditary Disease Foundation, the Abraham and Sonia Rochlin Foundation (Reno, NV), the Wolfson Foundation (UK), Neurocrine Biosciences Inc. (San Diego), and the Weizmann Institute of Science. The research team also included Hilda Slunt of Johns Hopkins School of Medicine, and James Gusella, chief of the Neurogenetics Laboratory, Harvard Medical School.

For more information: Ellen Shnidman, Weizmann Institute of Science, 76100 Rehovot, Israel. Tel: +972 8-934-2111 Fax: +972 8-946-6966. Email: ellens@acwis.org.