Abnormal Protein Linked to Neurological Diseases.
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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."
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."
posted by Valery Yermalitsky at
6:29 AM
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