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Lawrence Steinman, MD, PhD

Fig V-3: Lawrence Steinman

Dr. Steinman’s research has focused on the use of cystamine, a transglutaminase (TGase) inhibitor, as a potential treatment for Huntington’s Disease. Previous studies have shown that HD is associated with the formation of protein clumps, or aggregates, in the brain. Protein aggregation has been linked with some of the neurological symptoms of HD. (To learn more about protein aggregation, click here.) Earlier research has also shown that cystamine inactivates transglutaminase (TGase), an enzyme that helps produce these clumps of huntingtin protein. Therefore, Steinman and his former graduate student, Marcela Karpuj, PhD, reasoned that cystamine might control the disease by preventing the formation of huntingtin protein clumps.

Cystamine has been shown to inhibit the activity of TGase in two ways – one that flips the “off switch” and one that blocks huntingtin from binding. First, cystamine inactivates TGase through a disulfide-exchange reaction, a process by which proteins are activated or inactivated by the folding and unfolding of the amino acid chains that make the proteins. Second, cystamine competitively inhibits TGase. Since cystamine and huntingtin are both capable of binding to the same active site on the TGase enzyme, cystamine will block huntingtin from binding to TGase and thus limit TGase activity.

Steinman and Karpuj tested the effects of cystamine on mice that had a portion of the human HD allele of the Huntington gene (exon 1) inserted into their DNA. They knew that mice with exon 1 exhibited clinical pathologies very similar to the symptoms of human juvenile HD (including the presence of huntingtin protein aggregates and increased TGase activity in the brain), making them good test subjects for the study. (To learn more about juvenile HD, click here.)When cystamine was injected into the mice, TGase activity in the brain was reduced by up to 40% after only ten minutes. To test the effects of cystamine on the clinical symptoms of the HD mice, the drug was administered to mice that clearly demonstrated tremors and abnormal movement. Mice treated with cystamine generally exhibited fewer tremors, decreased abnormal movement, and a lower incidence and delayed onset of HD symptoms. They also lived 20% longer on average.

To the researchers’ surprise, however, cystamine did not reduce the number of huntingtin clumps in the brain. So although their hypothesized clinical outcomes were realized, their hypothetical mechanism was not. This unexpected finding led the Steinman lab to search for an explanation of the alleviated tremors and prolonged life. They started by looking for differences in gene expression between the mice that were treated with cystamine and the mice that were not. The researchers found two genes that were expressed much more in the cystamine-treated mice. A third, related gene showed increased activity in human HD patients, although not in the mice. All three genes code for proteins that are known to protect brain cells from damage. Therefore, cystamine seems to boost the levels of the brain’s natural protective proteins.

Although these findings suggest that cystamine could be a new treatment for HD, research for even more effective and specific drugs continues. Steinman suggests that a combination of cystamine and other drugs may have even greater benefits.

For more information on the research done by Lawrence Steinman, visit the following website:

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-J. Czaja 8-28-02