Drug treatment promising for halting Huntington's-related nerve death

January 31, 2005

DALLAS - Jan. 31, 2005 - Researchers at UT Southwestern Medical Center have discovered that drugs commonly used to treat psychiatric illnesses and blood disorders in humans may protect the brain cells that die in people with Huntington's disease, possibly delaying the onset and slowing the progression of the disease.

These findings, available online and in today's issue of Proceedings of the National Academy of Sciences, may offer new treatment options for Huntington's disease, which has no cure.

Huntington's disease is a neurological disorder in which the medium spiny striatal neurons, the nerve cells that control movement and certain mental functions die. Patients die within 10-15 years after onset of the disease.

The disease is caused by a mutation in the gene that makes the protein huntingtin. The mutation creates a long chain of the amino acid glutamine at one end of the protein. The length of the chain directly correlates with age of onset of the disease, with longer chains leading to symptoms earlier in life.

In previous studies, Dr. Ilya Bezprozvanny, associate professor of physiology at UT Southwestern, established that one of the defects that leads to death of nerve cells with the mutant huntingtin protein is improper regulation of calcium due to errant signals in the cells. Calcium is inappropriately released from its storage area in the cells, and eventually the cells die.

"We have developed a model that links the mutation in huntingtin with degeneration of motor neurons," Dr. Bezprozvanny said. "The model connects all the dots between the Huntington's disease mutation, defective calcium signaling in the cell, and subsequent degeneration of medium spiny striatal neurons."

In the current study, using the medium spiny neurons of mice that carry a copy of the mutated human huntingtin gene, Dr. Bezprozvanny and colleagues found that treatment of the cells in culture with the drug enoxaparin prevented inappropriate calcium release, and prevented cell death. Enoxaparin is an anti-coagulant that is FDA-approved in humans for use in treating blood clots.

Because the signals that lead cells to die can come from multiple pathways, Dr. Bezprozvanny then determined which cell death pathway affected the nerve cells carrying mutant huntingtin. He found that the nerve cells' mitochondria, the parts of the cell that create energy, released a protein called cytochrome c through a pore just before dying. From other studies, it was known the drugs nortriptyline and desipramine, which are antidepressants, and trifluoperazine, an antipsychotic, block the mitochondrial pore through which cytochrome c and other death signals are released. By treating the mouse nerve cells containing the mutant huntingtin protein with these drugs, Dr. Bezprozvanny was able to block the nerve cells from dying.

The next step, according to Dr. Bezprozvanny, will be to work with other researchers to test these drugs in whole animal models of Huntington's disease, and see if cell death and loss of motor function observed in these models can be prevented.

In addition, the researchers would like to expand their drug search beyond molecules that block calcium release and the mitochondrial pore. "We're looking for drugs that will prevent the pathological association of mutant huntingtin protein with the calcium signaling proteins in striatal neurons," he said. "We have a nice model system set up where we can easily look for cell death of Huntington's disease neurons, so we can look for the most specific drug with the least side effects."
Other UT Southwestern contributors to this study were Dr. Tie-Shan Tang, assistant instructor of physiology and Dr. Vitalie Lupu, postdoctoral researcher. In addition, Dr. Rodolfo Llinas of New York University School of Medicine, Dr. Bruce Kristal of Cornell University, and Dr. Michael Hayden of the University of British Columbia, who provided the mice used in the study, and members of their laboratories also contributed.

The study was funded by the Robert A. Welch Foundation, the Huntington's Disease Society of America, the Hereditary Disease Foundation, and the National Institute of Neurological Disorders and Stroke.

UT Southwestern Medical Center

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