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Genes, Toxins and Parkinson's Linda Carroll NYT Thursday, February 12, 2004 NEW YORK Parkinson's disease has baffled scientists ever since it was identified in the early 1800s. Although some evidence suggested that genes might have a role in causing the disease, for the most part old age was the sole characteristic that patients seemed to have in common. But in the past 20 years, with the discovery that chemical toxins and genetic mutations alike can lead to similar disorders, scientists are beginning to unravel the process that leads to the death of brain cells and, ultimately, rigidity, tremors and other symptoms of Parkinson's. "What we have learned in the last five years is just breathtaking," said Howard Federoff, a professor of neurology who is the director of the Center for Aging and Developmental Biology at the University of Rochester. "And my guess is that the pace will continue to accelerate." Many scientists now suspect that most Parkinson's cases are caused by interplay between an inherited genetic susceptibility and environmental toxins. But many of the insights have come from research into rare inherited forms of the disease. "All of these rare genetic forms of Parkinson's disease are giving us clues about a common pathway," said Peter Lansbury, an associate professor of neurology at Harvard. "If you interfere with that pathway in a big way - by a mutation, for example - then you're guaranteed to get Parkinson's. But if it's in a subtle way, you only increase a person's risk of developing the disease." Medications can treat the symptoms of Parkinson's, but none has been shown to slow the progression of the disease. In 1960, researchers discovered that symptoms were caused by the loss of the neurotransmitter dopamine through the deterioration of the substantia nigra, a small black oblong group of cells at the base of the brain. "Dopamine is like the oil in the engine of a car," said Clive Svendsen, a professor of anatomy and neurology at the Waisman Center of the University of Wisconsin. "If the oil is there, the car runs smoothly. If not, it seizes up." For years, scientists could not figure out why the cells were being damaged and dying. In 1982, researchers stumbled across a chemical, MPTP, that seemed to produce Parkinson's-like symptoms overnight. The chemical, a contaminant in some batches of heroin, left drug users rigid and slow. They had difficulty speaking and a shuffling gait, said J. William Langston, scientific director of the Parkinson's Institute in Sunnyvale, California, who first linked MPTP with Parkinson's. "They had all the features of advanced Parkinson's," he added. By linking MPTP to Parkinson's, researchers had the first inkling of what might be killing dopamine cells. MPTP is highly toxic to tiny crystalline structures, the mitochondria, which are the cells' power plants. When the mitochondria fail, Langston said, "it's like a blackout." Worse yet, when the mitochondria start to malfunction, they spew out toxic oxygen free radicals. That "causes much greater harm than the blackout," Langston said. The free radicals can corrode proteins in the cell and damage DNA. Once the link with mitochondrial damage had been found, the researchers began looking at chemicals with similar effects like the pesticide rotenone and the herbicide paraquat. Other researchers identified several Parkinson's genes. At least two appear to affect protein management. One is involved in creating a protein called alpha-synuclein; the other in tidying up excess or damaged copies of proteins. Scientists do not know exactly what alpha-synuclein does when it functions properly. But they are starting to understand what happens when the protein malfunctions. Mutations of the gene that encodes for alpha-synuclein appear to lead to misfolding of the protein, said John Trojanowski, the director of the Institute on Aging and a professor of geriatric medicine at the University of Pennsylvania. When a protein misfolds, it becomes useless and hard to dispose of, he said, comparing it to a piece of paper. "When it's scrunched up, it's not useful for reading or writing. Its function is lost. The same is true of proteins." Though none of the new research points to a clear road to a cure, Federoff said, understanding the basics of neuron death may pay off with better treatments. "Do I think there will be a cure in the next five to 10 years?" he asked. "No. But I believe that we will have strategies that will slow the progression of the disease. And for afflicted individuals, there will be a better quality of life." SOURCE: The New York Times / The International Herald Tribune, France http://www.iht.com/articles/129155.html * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn