Third Gene for Inherited Alzheimer’s Disease Found : Science: Researchers believe they have solved the mystery of the early-onset form of the disorder.
In a discovery that researchers hope will lead to the development of new treatments for Alzheimer’s disease, scientists have found the third defective gene that causes an inherited form of the disabling neurological illness.
The research team, headquartered at the University of Washington, also believes it is the final gene in the puzzle that is responsible for inherited Alzheimer’s, and that its discovery will allow them to assemble the pieces into a coherent picture of the disorder.
“This is an incredibly important discovery,” said neurologist Marcelle Morrison-Bogorad of the University of Texas, Southwestern Medical School in Dallas, a member of the Alzheimer’s Assn.’s Medical and Scientific Advisory Board. “This means that genetics has pretty much solved the mystery of early-onset Alzheimer’s disease, and it clears the path for scientific research that wasn’t there before.”
The new gene, reported today in the journal Science, is especially important, scientists believe, because it is surprisingly similar to another Alzheimer’s gene identified only six weeks ago.
The discovery of two nearly identical genes that cause the same disease is virtually unprecedented, scientists said, and strongly suggests that they play a crucial role in the onset of the disorder.
“It is extremely important that the new gene” is similar to a previously discovered gene, and that the proteins they produce are also similar, said neuroscientist Dennis Selkoe of Harvard Medical School, who was not involved in the research.
The existence of two distinct but very similar genes that cause the disease suggests that the genes, or others like them, play a crucial role in other forms of the disease as well, he said.
Inherited Alzheimer’s, which strikes victims in their 40s--10 to 20 years earlier than non-inherited Alzheimer’s--accounts for as much as 10% of the 4 million cases of Alzheimer’s among Americans.
Researchers are now working to figure out the exact function of the two proteins produced by the two genes and how that function is altered by mutations. And if they do, experts believe that they can quickly find drugs that will restore normal activity of the protein and prevent the progression of Alzheimer’s.
“If we can figure out what [the protein] is normally doing and why [this] mutation . . . can lead to Alzheimer’s, we’ve got something big on our hands,” said neuroscientist Creighton Phelps of the National Institute of Aging, which funded the research.
“Our knowledge of the molecular culprits in the disease has just increased dramatically,” said David J. Galas of the Darwin Molecular Corp. in Seattle, which identified the mutation in the gene. “The discovery will probably lead to a new class of treatments for the disease.”
The new gene, called STM2, was isolated from a small set of closely related families called the Volga Germans. They are descendants of a small group of Germans who settled along the Volga River in Russia in the 18th Century and then migrated to the United States earlier this century. The families have a very high incidence of inherited Alzheimer’s, which strikes early in life and progresses much more rapidly than the non-inherited form.
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Neuroscientist Gerard Schellenberg and his colleagues at the Veterans Affairs Medical Center and the University of Washington, both in Seattle, have been studying the Volga Germans for more than a decade.
Schellenberg’s team discovered the new gene shortly after a University of Toronto team had found another gene on chromosome 14, called S182. Schellenberg found that the two mutated genes were 67% identical. When biochemists at Darwin sequenced the gene, they found that it was altered at the same position in all the family members with Alzheimer’s and was normal in those who were healthy.
“The evidence is really tight that this is the right gene,” Galas said Thursday.
Researchers believe that they have now identified all the genes for inherited Alzheimer’s. All of the known families with inherited Alzheimer’s have a defect in one of the three genes that have been identified, NIA’s Phelps said, and between them, S182 and STM2 account for an estimated 95% of the known cases of inherited Alzheimer’s. The third gene, discovered in 1991, produces a defective form of a substance called amyloid precursor protein.
How these genes relate to the 90% of Alzheimer’s cases that are not inherited is still a mystery. Researchers have not yet reported finding any sporadic cases in which the genes are mutated, but they have only just begun looking. Some believe that there may be other, similar genes as well.
“I have never run across a situation in the genome where you have two [similar] genes like this and there are not others,” Galas said. “This flags the existence of a whole family of proteins that were hitherto unknown.”
“These other, as yet unknown, proteins, might cause the non-genetic forms of Alzheimer’s,” Phelps added.
Although researchers do not yet know the function of the two proteins, it is clear that they reside in the membranes of brain cells. They lace through the membrane seven times, hence the name second seven-transmembrane gene (STM2).
One of the best clues to their role comes from Harvard’s Selkoe, who has found that cells from patients with a defect in the S182 gene make abnormally high amounts of beta-amyloid.
Accumulation of beta-amyloid in brain cells is one of the principal hallmarks by which Alzheimer’s disease is diagnosed. Researchers are looking to see if the new gene does the same thing.
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A New Alzheimer’s Gene
The newly discovered Alzheimer’s gene is the blueprint for a protein that nestles in the outer membrane of brain cells, and is laced through the membrane seven times. To the surprise of researchers, that structure is virtually identical to the structure of a protein produced by another gene previously linked to the disorder.
Protein produced by defective gene
Cell membrane: 1, 2, 3, 4, 5, 6, 7
