REHOVOT, Israel ¿ An enzyme normally associated with skin formation and wound healing, localized in postmortem brains of patients with Huntington¿s disease (HD), may be the ¿smoking gun¿ behind this deadly inherited neurodegenerative disease, and inhibition a key to its cure.
Elevated activity of transglutaminase (TGase), with no sign of previously suspected amyloid protein, was found only in those areas of the brain known to have aggregations of the protein Huntington (htt).
This confirms a 1993 hypothesis by Howard Green, of Harvard Medical School in Boston, suggesting that TGase polymerizing enzyme might also act as a catalyst for aggregating the htt protein. Visibly clumped htt in the cortex, cerebellum and brain nuclei, but not in non-neural tissues, is considered a good pathological indicator for the disease.
The study, conducted in five postmortem brains of Huntington¿s patients between the ages of 30 and 80 and eight controls, was published in the June 22 issue of the Proceedings of the National Academy of Sciences by an Israeli-American team led by Lawrence Steinman (then of the Weizmann Institute of Science, now of Stanford University in Palo Alto, Calif.), and including his Weizmann Institute graduate student, Marcela Karpuj.
¿Lymphoid cells, as a convenient control tissue from healthy subjects and from Huntington¿s patients, showed no elevated TGase activity, leading us to believe that the enzyme is catalyzing the formation of the htt aggregates,¿ Steinman said.
These first-time activity measurements made in human brain tissue are a result of ¿Karpuj¿s determination in modifying techniques,¿ he said. Immunohistochemistry work ¿ by neuropathologists Donald Price at Johns Hopkins School of Medicine in Baltimore, and Mark Becher at the University of New Mexico Health Sciences Center in Albuquerque ¿ confirmed that the aggregates are not at all amyloid.
These combined results counter much-publicized in vitro and animal studies suggesting Huntington¿s is linked to the presence of amyloid bodies, which are formed by protein zippers. Steinman said no evidence of amyloid bodies was seen in the HD patients.
Yeda Research and Development Co Ltd., the commercialization arm of the Weizmann Institute of Science, filed on June 17 for worldwide patents for treatment of neurodegenerative disease with TGase inhibitors, Steinman said. He and Karpuj are listed as the inventors on the patent.