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---------------------------------------------------------------------------- In major advance, scientists discover cause of brain cell death ---------------------------------------------------------------------------- Copyright 1997 Nando.net Copyright 1997 N.Y. Times News Service (August 8, 1997 10:57 a.m. EDT) -- In a major medical advance, scientists have discovered what causes brain cells to die in people with Huntington's disease and six related disorders. The scientists said that in each case an insoluble ball of protein forms in the cell nucleus and kills it. Until now, the cause of cell death in these diseases had not been known. Huntington's disease is a mysterious, inherited malady in which portions of the brain known as basal ganglia atrophy and die. Victims develop an abnormal gait, as if being drunk, and suffer severe dementia. The related diseases, which are also inherited, include spinocerebellar ataxia and spinal and bulbar muscular atrophy. They affect different areas of the brain but produce similar symptoms. The new findings, by researchers in Britain, Germany and the United States, are described in two articles that appear Friday in the journal "Cell" and a third article in the August issue of the journal "Neuron." Researchers said they hoped to learn how to dissolve the balls of protein, thereby delaying or preventing the onset of the disease. "This is a pretty big deal," said Dr. David Housman, a biology professor at the Massachusetts Institute of Technology in Cambridge, Mass., who is an expert on Huntington's disease. "We have turned a corner from looking at genes to where we can begin developing real assays for drugs. If I were someone at risk for Huntington's disease this would be the biggest news I could imagine," although such treatments could be many years away. Dr. Allan Tobin, the scientific director of the Hereditary Disease Foundation in Santa Monica, Calif., and the director of the Brain Research Institute at UCLA, called the work "an important leap forward." "When we found the gene for Huntington's disease, our hope was that it would look like a smoking gun," Tobin said. "Now the problem looks like an alarm clock that has a bomb in it somewhere," adding that therapies should be able to defuse the bomb. The findings are exciting for biology, said Dr. Nancy Wexler, president of the Hereditary Disease Foundation, since they provide a common, underlying explanation for all neurodegenerative diseases, including Alzheimer's disease. A mutated gene underlies all Huntington's disease and the other six disorders, although each disease involves a different gene and different protein. Instead of losing bits of DNA, as happens in many common genetic disorders, the genes in these diseases develop long strings of excess DNA called "CAG repeats." In each disease, the additional DNA makes extra copies of glutamine, which is one of the building blocks for proteins. In the case of Huntington's disease, the process results in the production of a protein that contains a string of 35 to 100 glutamine building blocks. In its normal state, the same gene makes a protein with fewer than 35 glutamines in a row. The excess glutamine collects in the balls that clog the cells. For all of the diseases, the function of the normal versions of the proteins in the human body is not known, Housman said. But they are found in every cell of the body, as are the mutated proteins in patients with the diseases. Why the mutated proteins selectively kill only certain brain cells remains a mystery. The three new studies sought to determine how this happens. The first describes the creation of mice with a key portion of the human gene for Huntington's disease. Dr. Gillian Bates, a senior lecturer in molecular genetics at Guy's Hospital at the University of London, said she took a fragment of the Huntington gene with 150 "CAG repeats" and inserted it into fertilized mouse eggs. Some of the embryos took up the abnormal gene fragment in their chromosomes. The mice developed severe problems with gait and lost weight, just as people who have Huntington's disease do, Bates said. This mouse model of Huntington's made it possible to look closely at the abnormal protein during the disease process. In the same paper, Dr. Stephen Davies, an anatomy professor at University College London, reported the discovery of thick balls of the protein in the nuclei of cells within the mouse's basal ganglia and cortex. This was a surprise, Wexler said. No one had thought that Huntington's disease involved deposits in brain cells. Yet here was the abnormal protein "bunched up into a huge ball of crud inside the nucleus," he said. The second study, at the Max Planck Institute for Molecular Genetics in Berlin, involved test tube experiments. The researchers engineered Huntington's genes with 120, 80, 50, 30 and 20 "CAG repeats" and then made proteins from those genes. The proteins containing 50 or more glutamines fell into tight balls -- or more crud. The third study, done at the University of Pennsylvania in Philadelphia, found that the brains of patients with a form of spinocellebellar ataxia have clumps of abnormal protein in the nuclei of cells in their brain stem. Researchers have an idea of how these abnormal proteins gum up brain cells, Housman said. Long stretches of glutamine form protein sheets that are joined by especially strong positive and negative charges, he said. This configuration allows the protein, when it folds, to form a kind of zipper that cannot be broken, even with strong detergents or boiling water. <http://www.nando.net/newsroom/ntn/health/080897/health4_224.html> ---------------------------------------------------------------------------- [log in to unmask]