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| |  Large Subset Of Alzheimer's Cases May Be Maternally Inherited SAN DIEGO, April 29, 1997 -- Findings to be published in the April 29 issue of the Proceedings of the National Academy of Sciences link Alzheimer's disease with a specific set of mutations in mitochondrial DNA, which is maternally inherited. Scientists from MitoKor and its academic collaborators at the University of Virginia Health Sciences Center, University of California, San Diego and Harvard University, identified mutations in the cytochrome c oxidase genes of mitochondrial DNA (mtDNA) that may account for a large subset of the cases of late-onset Alzheimer's disease (AD). Alzheimer's disease is a progressive, degenerative disease of the brain that results in impaired memory, thinking and behavior. It is the fourth leading cause of death among adults, with approximately four million Americans afflicted with the disease. Symptoms include gradual memory loss, decline in ability to perform routine tasks, impairment of judgment and personality changes. The findings from this research may explain why the risk of AD increases when a maternal relative is afflicted with the disease. "Mounting evidence has suggested that defects in energy metabolism contribute to the pathogenesis of Alzheimer's disease," said Robert E. Davis, Ph.D., president and chief scientific officer at MitoKor. The scientists identified multiple specific point mutations in mtDNA that encode for two subunits or cytochrome c oxidase (COI and COII). Cytochrome C oxidase (CO) is an electron transport chain enzyme whose activity is decreased in the brain and peripheral tissue in late-onset Alzheimer's disease patients. "Because mitochondria are maternally inherited, we investigated the origins of these altered DNA molecules and noted significantly higher rates of AD-associated mitochondrial DNA molecules in children of affected mothers than of affected fathers,” Dr. Davis explained. This suggests that some cases of AD may be maternally inherited, he added. As part of the research, MitoKor developed proprietary cybrid (cytoplasmic hybrid) cell lines to model the mitochondrial DNA defects of Alzheimer's patients. To create these cell lines, human neuroblastoma cells were depleted of all their mtDNA, a procedure that produces a mitochondrial DNA knockout. Mitochondrial DNA from clinically defined Alzheimer's disease patients was then transferred into the cells. Because their original mtDNA was removed, these cells possessed only mtDNA from the AD patients. The cells were then cultured and found to express several key characteristics of Alzheimer's disease. "The mutations in COI and COII segregate as a unit, suggesting that mtDNA carrying these mutations is a unique, disease-associated mtDNA molecule," said W. Davis Parker, M.D., professor of neurology at the University of Virginia and senior author of the study. "The occurrence of these mutations in non- target tissues, such as blood cells, argues against the notion that these specific mtDNA mutations arise from the consequences of the disease state." "MitoKor has already developed an Alzheimer's diagnostic metric assay based on this research that is currently being used by major pharmaceutical companies to support late stage clinical trials of their anti-dementia therapeutics," said Walter H. Moos, Ph.D., chairman and CEO of MitoKor. "We plan on ultimately making this assay available for use as a confirmation of the clinical diagnosis of Alzheimer's, said Michele Le Gear, vice president of MitoKor. Mitochondria are the engines of the cell, producing most of the energy required for normal cellular function. They contain their own DNA, the only functional DNA found outside the nucleus in mammals. Mitochondrial DNA encodes a number of proteins involved in energy generation. Defects in mtDNA can change the expression of selected components in the electron transport chain, the main cellular energy-generating pathway, leading to cellular energy failure and ultimately disease. Neurons may be particularly vulnerable to such defects since they are high consumers of energy. MitoKor is a pharmacogenomics company focused on developing metrics and therapeutics for diseases caused or affected by abnormalities in the mitochondrial genome. Initial disease targets include, among others, Alzheimer's disease, Parkinson's disease, and diabetes mellitus (NIDDM).
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