3/25/98
MDA-BACKED RESEARCHERS UNCOVER NEW MECHANISM IN ALS
By Margaret Wahl, MDA Science Writer
Buildup of Glutamate Results From Cellular Processing Errors
An MDA-supported research team at Johns Hopkins University School of Medicine in Baltimore has uncovered a previously hidden but possibly very common mechanism to explain many cases of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). ALS is a rapidly progressive, degenerative disorder that involves the loss of motor-controlling nerve cells known as motor neurons. These cells are in the brain and spinal cord.
Neurologist and neuroscientist Jeffrey Rothstein, a longtime MDA grantee at Hopkins who also co-directs the MDA clinic at that institution, led the research team. Rothstein has been receiving MDA funding for several years to study the role of glutamate, a natural substance that carries signals between nerve cells but can be toxic under some circumstances. The only drug currently on the market for the treatment of ALS is riluzole (Rilutek), a glutamate inhibitor.
Researchers have known for some time that a phenomenon known as glutamate transport -- the clearing away of glutamate from the area between cells after it has transmitted a signal -- is often inadequate in people with ALS. This clearing process is normally accomplished by proteins known as glutamate transporters, one of which Rothstein had previously found to be deficient in many ALS patients. Now we understand why.
In a landmark paper published in the March 1998 issue of Neuron, the team found that the problem with an important glutamate transport protein known as EAAT2 isn't in a gene but, rather, is in the processing of the genetic message after the DNA, or gene, stage.
"These studies tell us two things," Rothstein said. "They explain why there is loss of the glutamate transporter in ALS and, perhaps more importantly, they provide us with a new mechanism for a neurodegenerative disease. It will be a great challenge to unravel this mechanism."
Mistakes Made On Path From Gene To Protein
The initial "code" for all proteins is found in the DNA, or genes, arranged on chromosomes in every cell. When there's a signal to manufacture a protein, the DNA code is transcribed into an RNA code; from there, the actual protein is made. RNA is the chemical step between DNA and a protein. RNA itself has multiple steps in its own processing. The final step leads to the final code, which is messenger RNA, or mRNA.
Rothstein has solid evidence that what goes wrong with the glutamate transporter EAAT2 in ALS is a problem in the processing of RNA so that the mRNA code for this protein is wrong.
Rothstein found one kind of garbled mRNA code for the glutamate transporter EAAT2 in 20 out of 30 tissue samples from people with ALS and found another kind of garbled mRNA for this protein in 11 out of the 30.
In another part of the study, garbled mRNA was found in the cerebrospinal fluid (CSF) in 12 of 18 patients. Rothstein said this finding might "provide us with a new diagnostic tool. A much larger study will be necessary to determine if the CSF analysis will be useful clinically."
These mRNA abnormalities weren't found in the control groups, which included people with other types of neurological disease.
Toxic Buildup Of Glutamate Follows Transporter Loss
The garbled mRNA codes decrease the amount of effective glutamate transport protein, which decreases glutamate removal from the area around motor neurons. Such transport deficiencies probably lead to a toxic buildup of glutamate and to the development of degeneration of motor neurons in the brain and spinal cord, the hallmark of ALS. In the brain, the mRNA abnormalities were specific to those areas that degenerate in ALS.
The findings support the current use of glutamate inhibitors such as riluzole in the treatment of ALS and indicate the need for further studies of glutamate transporters and of RNA processing mechanisms that affect these proteins. Such studies could lead to better treatments.
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