TDP-43 Linked to ALS & Frontotemporal Dementia

[Jared]

Abnormal Protein Linked to 2 Neurological Diseases By Ed Edelson
HealthDay Reporter
35 minutes ago


THURSDAY, Oct. 5 (HealthDay News) -- Researchers have identified the abnormal protein common to two devastating neurological diseases -- Lou Gehrig's disease, which causes death by paralysis, and frontotemporal dementia, which starts with bizarre behavior and has a destructive effect on mental function comparable to Alzheimer's disease.

The protein is prosaically designated TDP-43, according to a report in the Oct. 6 issue of Science led by researchers at the University of Pennsylvania School of Medicine. When it folds abnormally, the protein should be quietly removed from the brain. But in some people, the removal system doesn't work, and the protein accumulates inside brain cells. The damage done depends on where the accumulation occurs.

"This provides a beginning of an area of investigation with the goal of trying to turn it into something useful, first as a biomarker and eventually as a target of therapy," said study leader Virginia Lee, director of the university's Center for Neurodegenerative Disease Research.

It has long been thought that the two conditions are somehow related, Lee said. The TDP-43 protein provides the common thread. When its abnormal form accumulates in cells of the frontal and temporal lobes -- the brain areas that control judgment and comportment -- the result is frontotemporal dementia (FTD). When the accumulation is in the spinal cord cells, which control movement, the result is Lou Gehrig's disease, whose formal name is amyotrophic lateral sclerosis, she said.

The incidence of Lou Gehrig's disease is one in 100,000 Americans, Lee said. The incidence of FTD is unknown because it usually is treated as a psychiatric disorder, but it is believed to be the second most common form of dementia, behind Alzheimer's disease.

The researchers used an immunological approach to isolate the protein, Lee said. Their knowledge of other abnormal proteins in neurological diseases, such as beta amyloid in Alzheimer's, made them believe it had a high molecular weight and was highly insoluble.

Working with brain tissue from people who had FTD, the researchers got rid of low-molecular-weight, soluble proteins. They injected what was left into mice, whose immune systems generated antibodies against the material. Work with more than 50,000 tissue samples eventually pointed to TDP-43, a finding confirmed with the use of commercially available antibodies against the protein.

Research yet to be done will focus on why the protein becomes abnormal in the first place and why the body's disposal system doesn't work properly, Lee said.

Stephen Snyder is a program director in the Neuroscience and Neuropsychology of Aging Program at the National Institute on Aging, which funded the new work. "This paper shows a signature protein," he said. "This is exactly the kind of finding that moves us ahead quickly."

But "quickly" has a distinct meaning in the study of neurological diseases, Snyder said. It has been a quarter century since the role of beta amyloid in Alzheimer's disease was discovered, yet work to develop treatments for the disorder is still under way, he said.

"The neurodegenerative-disease nut cracks open grudgingly," Snyder said. "But all that we have learned with Alzheimer's disease will come into play here. The finding of this particular protein in lesions of these different diseases, that has to count for something. It gives us a mechanism involved in these devastating diseases. How it is involved is an interesting thing to look at."

[Lorainemarie]

http://www.philly.com/mld/philly/entertainment/family_guide/15690317.htmPosted
Posted on Fri, Oct. 06, 2006

Key link discovered in dementia, ALS
A protein buildup is tied to two ills.
"It's huge," an expert said of the find by Penn scientists.

By Tom Avril
Inquirer Staff Writer

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 those associated with Gehrig's, gradually losing control of their muscles.


http://www.philly.com/images/philly/inquirer/15697/246399543886.jpg
Gerald S. Williams/Inquirer
Adam Truax and Jennifer Bruce use a microscope and computer monitor to look at a slide of diseased protein in brain tissue sample from a patient with Frontal Tempotral Dementia.


Today, a team led by University of Pennsylvania scientists says that is no coincidence. 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 Huntingdon's, among others. Cures remain years away, but pinpointing an apparent culprit is a major step toward fighting it.

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, experts say. That's partly because it can lead to criminal or sexually deviant behavior, and some people may never be diagnosed. Also, it sometimes may be misdiagnosed as a psychiatric illness.

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 are not 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 were 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.

Lee's team first extracted diseased tissue from several brains donated by deceased dementia patients, said Penn's Linda Kwong, one of three lead authors of the paper.

The extract was injected into mice, causing their immune systems to develop numerous types of antibodies. The mouse antibodies were then added to diseased human brain samples and they attached to the mysterious protein clumps, which could then be stained and become visible.

The researchers then extracted more tissue from the same regions of the original brains, which contained a variety of proteins.

To isolate which protein had reacted with the antibodies, they separated the proteins and tested the antibodies on each.

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 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 had lots of questions to answer: 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?

Any one of these steps would be a potential target for new treatment.

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

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

Lee said she was excited because discoveries such as hers and Hutton's were becoming more common with today's techniques, in what she called an "explosion of information."

While some scientists had suspected a connection between certain dementias and ALS, Lee said she had hardly dared to hope. But when her slides with brain samples tested positive for the protein again and again, she and her team raced to finish the work before someone else beat them to it.

"A lot of things you hope and you hypothesize, don't come true," Lee said. "This time, it came true."

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Also see: "Probing the Mind for a Cure," a multimedia story about a patient who gave his brain to Penn's lab, is at http://go.philly.com/brain

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Contact staff writer Tom Avril at 215-854-2430 or tavril@phillynews.com.