A link between Alzheimer's disease and mutations in mitochondrial DNA (mtDNA) arose from a flawed lab procedure, according to two reports in the current Proceedings of the National Academy of Sciences (PNAS). A scientist involved in the original work acknowledges his study was flawed, but insists that damaged mitochondria play a role in the neurodegenerative disease.
Since the early 1990s, several research teams have found that Alzheimer's patients have lower levels of key enzymes produced in mitochondria, tiny power plants within cells that harbor their own genetic instructions apart from nuclear DNA. That deficiency in the brain appears to contribute to cell death. These findings prompted Robert Davis and co-workers at MitoKor, a San Diego-based biotech firm, to look for mutations in the mtDNA of Alzheimer's patients. In the 29 April PNAS, Davis' team concluded that Alzheimer's patients were at least three times as likely as healthy individuals to carry mutations in one of two mitochondrial genes.
Now it appears that what Davis thought were mutations are actually "pseudogenes" --bits of nuclear DNA that resemble working genes but don't churn out proteins. The MitoKor team isolated mtDNA using an unconventional approach of boiling and cooling cells. Neurologist Michio Hirano and his colleagues at Columbia University duplicated the procedure in three kinds of cells--brain cells from Alzheimer's patients and healthy people, as well as cells dubbed r0 that lack mitochondria. They found the same DNA stretches resembling mtDNA all three kinds of cells, suggesting that the DNA was in fact from the nucleus. Hirano's team further determined that the apparent genes did not code for proteins, and concluded that these are pseudogenes, evolutionary castoffs similar to the appendix. A similar study in PNAS by Emory University researchers came to the same conclusion. The MitoKor team mistook the nuclear DNA for mitochondrial genes coding for the cyclooxygenase (COX) enzymes, says Davis, because the two sequences differ by only 2%.
"We misinterpreted the original data," acknowledges Davis. But he adds that evidence of a link between mtDNA and Alzheimer's remains strong. Since their original work, Davis and his colleagues have gathered more evidence that defective mitochondrial COX enzymes are more likely to be found in Alzheimer's patients than in healthy individuals. "We have not found the mutations that cause the COX defects," says Davis. "But there's something still unknown in the mitochondria and mtDNA that's connected to COX activity and Alzheimer's."