This news about Huntington’s Disease was announced yesterday. Excerpts: “Scientists have solved a mystery surrounding a horrific illness: Why people with Huntington’s disease harbor a faulty protein throughout their bodies but it destroys only certain brain cells. … [That’s] the connection to other brain-destroying diseases… Most are distinguished by clumps of some type of faulty protein, and there’s a raging debate among scientists about whether the clumps, also called ‘aggregates,’ are the cause of brain destruction or a frantic attempt by the brain to save itself. ‘The answers in one disease may have implications for another,’ noted Koroshetz of NIH’s National Institute of Neurological Disorders and Stroke. ‘There’s been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem’.”
The protein involved in PSP and CBD is tau.
Two, similar articles are copied below. (I read one on an MSA-related online discussion group.)
http://hosted.ap.org/dynamic/stories/U/ … NS_MYSTERY
Jun 4, 2:00 PM EDT
Scientists uncover culprit in Huntington’s disease
By LAURAN NEERGAARD
AP Medical Writer
WASHINGTON (AP) — Scientists have solved a mystery surrounding a horrific illness: Why people with Huntington’s disease harbor a faulty protein throughout their bodies but it destroys only certain brain cells.
The discovery may provide a long-awaited target for developing treatments for the incurable killer – and also may have ramifications for more common brain diseases like Alzheimer’s.
“Up until now, nobody had the vaguest notion of what was the cause of the brain damage and the death,” said Dr. Solomon Snyder of Johns Hopkins University, whose team reported the findings in Friday’s edition of the journal Science.
“This is a significant step forward,” said Dr. Walter Koroshetz, deputy director of the National Institutes of Health’s brain division.
Huntington’s is a rare inherited disease – there are an estimated 30,000 U.S. patients – that typically strikes in the late 30s or early 40s. What starts as uncontrollable twitches and jerks and deterioration of mental abilities inexorably worsens until patients can barely eat, speak or walk. Death occurs a decade or more after symptoms begin.
One mutated gene is the cause. A child of a Huntington’s patient has a 50-50 chance of inheriting that gene, and anyone who does will develop symptoms at some point if they live long enough. Scientists discovered the gene in 1993, giving families the hard choice of whether to be tested to learn who escaped that fate and who didn’t.
But 16 years later, there is only one treatment to ease the writhing movements and little progress toward the bigger goal – finding some way of slowing or stopping the disease from carving a hole in patients’ brains.
Enter the new research. The bad Huntington’s gene creates a faulty protein that’s found in all cells. Yet the only cells that die are certain neurons, mostly those in a movement-controlling brain region called the corpus striatum that by the time patients die is so ravaged that it’s tissue-paper thin.
Why? A second protein is the culprit, Snyder’s team discovered. It’s a little-known molecule named Rhes that is found almost exclusively in the striatum. When Rhes mixes with the mutated Huntington’s protein it sparks a chemical reaction, the researchers reported.
First came a simple experiment: They used human embryonic cells and brain cells taken from mice. To each, they mixed in different combinations of the mutated Huntington’s protein, its normal version, and Rhes. Only when both the mutant protein and Rhes were in the same cells did those cells start dying.
Then the researchers teased out just what made the chemical reaction, named sumoylation, so toxic. It seems that cells may try to deal with the mutated protein by clumping it out of the way, almost like creating a garbage heap. Adding Rhes led to less clumping along with cell death, suggesting that it’s the soluble form of the faulty protein that’s dangerous.
And that’s the connection to other brain-destroying diseases like Alzheimer’s. Most are distinguished by clumps of some type of faulty protein, and there’s a raging debate among scientists about whether the clumps, also called “aggregates,” are the cause of brain destruction or a frantic attempt by the brain to save itself.
“The answers in one disease may have implications for another,” noted Koroshetz of NIH’s National Institute of Neurological Disorders and Stroke. “There’s been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem.”
Dr. Nancy Wexler of the Hereditary Disease Foundation, who helped lead the Huntington’s gene discovery, called the work a “fabulous experiment” and praised the Hopkins team for quickly publishing the Rhes reaction so that other researchers could start hunting ways to block it.
“This is a very promising avenue,” she said.
One next step is to see whether removing Rhes from mice with Huntington’s disease slows or prevents the brain cell death without causing too many side effects. If so, the quest would be for a drug to block that protein.
© 2009 The Associated Press.
http://www.sciencedaily.com/releases/20 … 144330.htm
Mystery Solved: Tiny Protein-activator Responsible For Brain Cell Damage In Huntington Disease
ScienceDaily (June 5, 2009) — Johns Hopkins brain scientists have figured out why a faulty protein accumulates in cells everywhere in the bodies of people with Huntington’s disease (HD), but only kills cells in the part of the brain that controls movement, causing negligible damage to tissues elsewhere. The answer, reported this week in Science, lies in one tiny protein called “Rhes” that’s found only in the part of the brain that controls movement. The findings, according to the Hopkins scientists, explain the unique pattern of brain damage in HD and its symptoms, as well as offer a strategy for new therapy.
HD itself is caused by a genetic defect that produces a mutant version of the protein “huntingtin” that gathers in all cells of the body, but only seems to affect the brain. Passed from parent to child through an alteration of a normal gene, HD over time causes irreversible uncontrolled movement, loss of intellectual function, emotional disturbances and death.
“It’s always been a mystery why, if the protein made by the HD gene is seen in all cells of the body, only the brain, and only a particular part of the brain, the corpus striatum, deteriorates,” says Solomon H. Snyder, M.D., professor of neuroscience at Johns Hopkins. “By finding the basic culprit, the potential is there to develop drugs that target it and either prevent symptoms or slow them down.”
Curious about the huntingtin protein’s striatal-specific effect, Snyder’s research team, led by Srinivasa Subramaniam, Ph.D., a postdoctoral fellow, searched for proteins that interacted locally, specifically and exclusively with huntingtin in the corpus striatum, guessing that the molecular answer to the mystery most likely would be found there.
The protein Rhes caught their attention because they already were studying a related protein for other reasons. Rhes was known to be found almost exclusively in the corpus striatum.
Conducting tests using human and mouse cells, they found that Rhes interacted with both healthy and mutant versions of huntingtin protein, but bound much more strongly to mutant huntingtin, also known as mHtt.
“Touching or binding is one matter, but death is altogether another,” said Snyder, so the next step was to see whether and how Rhes plus mHtt could kill brain cells in the corpus striatum.
Using human embryonic cells and brain cells taken from mice the researchers added different combinations of normal and mutant huntingtin and Rhes, and examined the cells over the next week to see if any cells died.
While each protein alone didn’t change the number of cells in the dishes, when both mHtt and Rhes were present in the same cells, half the cells died within 48 hours.
“Here’s the Rhes protein, we’ve known about it for years, nobody ever really knew what it did in the brain or anywhere else,” says Snyder. “And it turns out it looks like the key to Huntington’s disease.”
Snyder’s team then went on to tackle another mystery surrounding the disease, the solution to this one adding further evidence for the role Rhes plays in HD.
“We’ve known for a long time that abnormal huntingtin proteins aggregate and form clumps in all cells of the body, but the corpus striatum of HD patients seems to have fewer of these clumps than other brain regions or the rest of the body,” says Subramaniam in describing the mystery. “This has led to much controversy: Are the clumps toxic, or is it the lack of clumps that’s toxic to these brain cells?”
In their experiment, adding Rhes to cells with abnormal huntingtin led to fewer clumps, but the cells died. The results, says Subramaniam, suggest that Rhes might be responsible for unclumping mutant huntingtin protein and this somehow kills cells. “Since Rhes is highly found in the corpus striatum, clumping somehow protects cells in other tissues of the body from dying,” says Subramaniam.
Subramaniam and the rest of Snyder’s research team currently are exploring whether removing Rhes from mice with Huntington’s disease can slow or stop brain cells from dying.
“Now that we’ve uncovered the role of Rhes, it’s possible that drugs can be designed that specifically target Rhes to treat or even prevent the disease,” says Snyder.
This study was funded by a U.S. Public Health Service grant and Research Scientist Award.
Authors on the paper are Srinivasa Subramaniam, Katherine Sixt, Roxanne Barrow and Solomon H. Snyder, all of Johns Hopkins.
Adapted from materials provided by Johns Hopkins Medical Institutions, via EurekAlert!, a service of AAAS.
