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Scientists identify protein linked to ALS

Clumps in brain seen in dementia, Gehrig's disease

PHILADELPHIA -- Doctors have known for years that some people with Lou Gehrig's disease also suffer from a type of dementia. And some with that dementia also develop crippling symptoms like Gehrig's, gradually losing control of their muscles.

Today, a team led by University of Pennsylvania scientists reports the discovery of a likely culprit in both.

The two distinct diseases are marked by an abnormal accumulation of the same protein -- a startling two-for-one discovery described in the journal Science.

``It's huge," said Mike Hutton, a neuroscientist at the Mayo Clinic College of Medicine in Jacksonville, Fla., who was not involved with the study.

``It completely changes the way in which I think ALS research will focus," he added, using the abbreviation for amyotrophic lateral sclerosis, the disease that felled Gehrig.

With this find, science has now identified at least one faulty protein associated with each of the major neurodegenerative diseases -- Alzheimer's, Parkinson's, and Huntington's, among others. Cures remain years away, but pinpointing the apparent culpritsis a major step toward fighting them.

The dementia in the new research is a type of frontotemporal dementia, marked by toxic clumps of proteins in the brain's frontal and temporal lobes, which control judgment and behavior. It is less common than Alzheimer's and tends to strike younger people.

It is unclear how many thousands of people have it. That's partly because it can lead to criminal or sexually deviant behavior, and some people may never come to the attention of doctors because they are in prison.

ALS is diagnosed in 5,600 people in the United States every year, and up to 30,000 have it at any given time, according to the nonprofit ALS Association. It is almost always fatal.

Scientists aren't certain whether the protein accumulations described in Science directly cause either disease or merely play a supporting role.

But Virginia Lee, a neurobiologist at Penn's School of Medicine and the report's senior author, said they are clearly part of a cascade of events that leads to disease.

``It's on the direct pathway," said Lee, who collaborated with 12 other Penn scientists, including her husband, John Trojanowski, and researchers in California, Canada, and Germany.

Pathologists previously had observed protein clumps, called ``inclusions," in the brains of people with ALS and frontotemporal dementia. But actually identifying the protein was a laborious process that took five years.

The culprit: a previously known protein called TDP-43.

TDP-43 is normally present in the nuclei of healthy brain cells, and is believed to play a role in transcribing the genetic code. In sick patients, however, it shows up as clumps in unusual places: usually outside the nucleus but sometimes in an odd, lens-shaped clump inside.

The researchers found TDP-43 clumps in all 53 brains with frontotemporal dementia they examined.

They also found it in all 18 cases of ALS that apparently had not been inherited; the protein was present in some patients who had a family history of ALS.

Still unclear is what genetic mutation or mutations lead to these malfunctions. There are several candidates, including a dementia mutation discovered just three months ago, by the Mayo Clinic's Hutton. But it has no direct impact on TDP-43; Hutton said it may set off a chain of events that leads to the TDP-43 clumps.

Penn neurogeneticist Paul Taylor, who was not involved with the new paper, said researchers have lots of questions to answer.

For instance, how does the protein harm the brain cell? Is it a failure to carry out its correct function, or are the clumps themselves toxic? Does some mutation cause the clumps to form, or does some flaw prevent them from being cleared away?

Answers to any of these questions could provide a potential target for new drugs.

While a medicine would be years away, Taylor called the new paper, which was funded by the National Insitute on Aging, ``highly significant."

``It opens the door to trying to find out how the whole thing is working," he said.

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