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I found the following at: http://www.pslgroup.com/dg/cf4e.htm. Jackie ________________________________________ Genetic Defect May Point to Heredity as a Source of Parkinson's Disease ------------------------------------------------------------------------ CHARLOTTESVILLE, Va., Oct. 11, 1996 -- A specific genetic defect that may cause Parkinson's disease has been identified by scientists at the University of Virginia and MitoKor, a California-based biopharmaceutical company, according to a study published in the October issue of the Annals of Neurology. "There is a piece of DNA that doesn't play by the rules," said W. Davis Parker, professor of neurology at U.Va. and leader of the research team. "The genes contained on mitochondrial DNA (mtDNA) exist independent of nuclear DNA. In other words, this is a new principle of human genetics that may explain why some diseases currently thought of as sporadic, like Parkinson's, may in fact be inherited in an unorthodox way." The scientists found that the genetic defect affects a mitochondrial enzyme called complex I. Although scientists have suspected for the past seven years that the complex I defect is a key factor in the onset of Parkinson's, they did not know the origin of the defect. The U.Va/MitoKor team found that the complex I defect arises from mitochondrial DNA and interferes with the function of mitochondria -- thousands of thread-like bodies in each cell which contain enzymes for the production of energy. "Complex I, which is abnormal in Parkinson's patients, is a bioenergetic enzyme that serves as the principal starting point of the electron transport chain, the energy generating mechanism found in the mitochondria of each cell," said Robert E. Davis, chief executive officer of MitoKor and a co-author of the study. "We believed that a mitochondrial rather than a nuclear genetic mechanism was at work in Parkinson's." To test the theory, the researchers developed proprietary cybrid (cytoplasmic hybrid) cell lines to model the mitochondrial DNA of Parkinson's patients. First, human neuroblastoma cells -- embryonic cells derived from the neural tube that give rise to neurons -- were depleted of all their mtDNA. Mitochondrial DNA from 24 Parkinson's patients was then transferred into those cells, the resulting cell lines were cultured. Cybrid cell lines possessing mtDNA from 28 non-Parkinson's patients were used as the normal controls. The scientists then performed a series of biochemical assays on the cybrid cell lines, measuring cytochrome oxidase activity and complex I activity, the key elements within the mitochondrial electron transport mechanism. They also analyzed for the production of oxygen radicals and the effects of a parkinsonism-inducing toxin called MPTP, a contaminant of an illegally prepared heroin-like narcotic. Complex I activity was 20 percent lower in the Parkinson's disease (PD) cybrids as compared to the controls. Additional research demonstrated that the genetically encoded complex I defect of Parkinson's disease serves as a source of oxygen radical generation. Oxygen radicals are widely believed to play a role in the death of neurons in neurodegenerative diseases like Parkinson's, Alzheimer's and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Also, cells containing Parkinson mtDNA were more susceptible to an MPTP derivative. This indicates that even though the enzyme defect is genetic, environmental toxins could still contribute to the disease's development. "While the genetically determined complex I defect in Parkinson's disease may itself be sufficient to produce the disease, our research does not rule out the importance of external toxins in the disease process," said Dr. Russell Swerdlow, U.Va. neurologist and lead author of the study. "The observation that a specific biochemical defect can render cells more vulnerable to MPTP toxicity illustrates how interactions between an environmental mitochondrial toxin and an apparent mtDNA defect could accelerate neurodegeneration. This may explain why some individuals develop Parkinson's disease following toxin exposure, while others similarly subjected to the same toxin at the same dose do not." The U.Va./MitoKor team's next step will be to characterize the exact mtDNA mutations that may lead to Parkinson's disease. "We are conducting further mutational analysis of the mtDNA of Parkinson's disease patients," Davis said. "Once the defect or defects are known, we'll be working to develop a therapeutic agent that reverses the complex I defect." MitoKor, a development-stage biopharmaceutical company in San Diego, Calif., is the only company in the United States whose sole focus is the role of mitochondria in human disease. Their proprietary technology is leading the way in the commercialization of pharmaceutical and diagnostic products targeted to treat Alzheimer's, Parkinson's, diabetes mellitus (NIDDM) and schizophrenia. MitoKor was formed in 1992 under the name Applied Genetics.