Faulty Wiring in Brain's Powerhouses NCRR Reporter Nov/Dec 1995 Just as a computer receiving too much or too little power might burn out or malfunction, the brain's relay stations called neurons can shut down or lower their output if they don't receive sufficient energy. Thinking along these lines, researchers studying neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's, are considering the possibility that some of the symptoms of these disorders might originate from fundamental errors in the brain's power grid. Within the last few years, Dr. Douglas C. Wallace and his colleagues at Emory University School of Medicine in Atlanta, Georgia, have found mutations, or changes, in the structure of DNA in the brain's powerhouses known as mitochondria that might help illuminate the causes of several debilitating diseases. Their studies were conducted at Emory's Microchemical Analysis Facility for Molecular Biology, with instrumentation purchased through NCRR's Shared Instrumentation Grant (SIG) Program. Mitochondria are small energy-producing structures present in the cytoplasm of all cells in the body. The energy, contained in a chemical compound called ATP, fuels numerous processes in the brain as well as the rest of the body. Without ATP, the human body's machinery would come to a grinding halt. Raw materials for ATP production, such as glucose, must be imported from cytoplasm by the mitochondria. But many required tools enzymes and RNA are manufactured within the mitochondria, specified by mitochondrial genes. By analyzing the DNA of those genes, the Georgia scientists have found mutations that might be related to the occurrence of some neurodegenerative diseases. Mitochondrial DNA is different from the nuclear DNA that carries most of our genes. Its function is also more affected by minor damage than is its nuclear counterpart because it has a limited capacity for self- repair. Mitochondrial DNA is inherited maternally, so potentially damaging mutations may accumulate over many generations. In a recent study Dr. Wallace and his colleagues found that the mitochondrial DNA in the brains of 22 patients with Huntington's disease was structurally different from the mitochondrial DNA of 25 age-matched control individuals. The brain tissues from the frontal, occipital, and temporal cortical lobes and putamen were obtained by autopsy. The researchers found that a particular deletion mutation loss of 5,000 nucleotide pairs in the double-stranded DNA was elevenfold more frequent in the temporal lobes and fivefold more frequent in the frontal lobes of the patients with Huntington's disease than in the controls. But in the occipital lobe and putamen, the results were comparable in patients and controls. The researchers do not know why the mitochondrial gene mutation was not seen in the occipital lobe or putamen. But they suggest that these areas of the brain might have suffered greater losses of neurons and consequently greater loss of DNA during the progression of the disease than the temporal lobes and cortex. As a consequence, the DNA deletion levels might normalize in these brain areas during the terminal stages of the disease, they say. Dr. Wallace notes that the primary symptoms of Huntington's disease (movement disorders and dementia) are caused by malfunctioning basal cell ganglia, located in the putamen, where a large proportion of cells may be lost. In contrast, more cells in the other two brain areas survive during disease progression and can display the high degree of mitochondrial DNA mutation. Scientists' interest in mitochondrial mutations date back to 1988, when the Emory researchers detected a particular mutation in mitochondrial DNA that was associated with an eye disease known as Leber's hereditary optic neuropathy. Since that finding, mitochondrial DNA mutations have been shown to be involved in a host of degenerative diseases, ranging from blindness, heart disease, and diabetes to movement disorders and dementia. Dr. Wallace's detection of mitochondrial DNA mutations in patients with Huntington's disease came on the heels of similar findings in the brains of Alzheimer patients. The investigators also discovered that a single nucleotide change was present in a particular gene in approximately 5 percent of 173 Alzheimer patients but only in 0.7 percent of the general population. Researchers at the University of California, Los Angeles, recently reported that they too had found the same mutation in 8.3 percent of 72 patients with Alzheimer's disease but in only 0.34 percent of 296 age-matched controls. Nevertheless, other scientists have been unable to confirm the high mutation rates in Alzheimer patients. "I think our work is valid, but there have not been enough independent trials that have reproduced the results and pinned them down completely," says Dr. Wallace. In addition to limiting the supply of ATP, mitochondrial mutations might also result in production of a type of toxic substance called oxygen free radicals. These compounds can damage DNA and cause extensive havoc in sensitive neurons. Dr. Wallace and his colleagues have not yet been able to prove a direct cause-effect relationship between a mitochondrial DNA mutation and the symptoms of Alzheimer's or Huntington's disease. But in dystonia muscle rigidity associated with basal ganglia damage their DNA sequencing studies led them to one particular mitochondrial DNA mutation that was handed down from mother to daughter through several generations. "Dystonia is remarkably similar to Huntington's or Parkinson's diseases. It just occurs a little earlier," Dr. Wallace says. "While Huntington's disease is inherited through a nuclear gene, we now show an inherited mitochondrial DNA mutation for dystonia, which is absolutely unequivocal. "Our data say that movement disorders can be due to mutations in mitochondrial DNA. They provide a superb foundation from which to move out to the next level, which is the Alzheimer's mutation." Ole Henriksen, Ph.D. and Alan G. Morton The studies described in this article were supported by a National Center for Research Resources Shared Instrumentation Grant; the National Institute on Aging; the National Institute of Neurological Disorders and Stroke; the National Heart, Lung, and Blood Institute; and the Muscular Dystrophy Foundation. Additional Reading 1. Horton, T. M., Graham, B. H., Corral-Debrinski, M., et al., Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients. Neurology, in press. 2. Johns, D. R., Mitochondrial DNA and disease, New England Journal of Medicine 333:638-644, 1995. --- Internet : [log in to unmask] Telephone: +1-602-860-1121 FAX : +1-602-451-1165 Web : http://www.stat.com/~david John Cottingham "The parkinsn list brings Knowledge, Comfort, Hope, and Homeboy Friendship to the parkinsonian world." LibraryH Parkinson's Chat on the Undernet 8:30 PM CST -6 Daily. 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