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In major advance, scientists discover cause of brain cell death
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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.

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