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NEUROLOGY Dopamine May Play Dual Role in Parkinson's DiseaseA team of HMS researchers may be closing in on an answer to a conundrum that has dominated Parkinson's research for nearly five years. Among the telltale signs of the disease are the dense dots of protein that appear inside cells in the substantia nigra, a key area in the brain for control of movement. But it has been unclear what tale the intruders, the Lewy bodies, are telling. Unlike the amyloid plaques of Alzheimer's disease, which abound in the brain of an advanced Alzheimer's patient, Lewy bodies appear only sparingly--and often in cells that appear to be healthy.
Dopamine stabilizes a possible Parkinson's disease culprit. The discovery helps to solve several outstanding puzzles, says Peter Lansbury (right), with co-author Jean-Christophe Rochet. Photo by Steve Gilbert Are Lewy bodies killing the cells, thereby bringing about the motor deficits that characterize Parkinson's disease? Or are they actually do-gooders, protecting neurons? If the latter, what is the real culprit? A year ago, Peter Lansbury and his colleagues reported that the fibrils of alpha-synuclein that make up Lewy bodies arise from a less stable form. They suggested that these precursors were the real villains. A stumbling block in the hypothesis was that precursors, or protofibrils, are notoriously unstable and might convert to the fibrillar form before wreaking havoc in the cells of the substantia nigra. It now appears that these protofibrils are stabilized by a highly available, if surprising, molecule--namely, the cells' primary chemical messenger, dopamine. Lansbury, HMS associate professor of neurology at Brigham and Women's Hospital, and his colleagues found that the normally flighty protofibrils were made more stable when mixed with any one of 14 dopamine-related compounds in vitro. Their findings appear in the Nov. 9 Science. Research fellows in neurology Kelly Conway and Jean-Christophe Rochet are lead co-authors on the study. The next step will be to see if the protofibrils are stabilized by dopamine in animals and, if so, whether they cause disease, a project Lansbury is currently undertaking in collaboration with Mel Feany, HMS instructor in pathology at BWH. But Lansbury says the preliminary findings are consistent with his hypothesis that protofibrils are to blame in Parkinson's. "It's the earliest things that are the problem, while the Lewy bodies are evidence of success, that the cell was able to make fibrils fast enough and was able to survive," he said. In fact, the fibrillar form may be protective since fibrils consume protofibrils as they form. Tying Another Loose EndThe discovery that dopamine may stabilize potentially toxic protofibrils could shed light on another puzzle. Unlike Alzheimer's disease, which affects a wide array of neurons, Parkinson's sets its sights on only the dopamine-producing cells of the substantia nigra. Researchers have long searched for a way to explain the disease's specificity. The possibility that the protofibrils may require dopamine's calming influence to carry out their destructive activities could provide such an explanation.While the new findings answer a pair of old questions, they also pose a fresh dilemma. For years, the main strategy for treating Parkinson's disease has been to replace the dopamine that is lost through the death of dopaminergic neurons. It is a strategy that appears to alleviate many of the symptoms of the disease, at least for awhile. But the discovery that dopamine conspires with potentially toxic protofibrils suggests that this approach might have drawbacks. Indeed, other in vitro studies have suggested that dopamine has negative effects. "This could be one element of dopamine toxicity," said Lansbury. "It tells you if you want to optimize dopamine therapy, this is one part of dopamine's activity you would want to get rid of."
The many faces of a protein. Unfolded alpha-synuclein (top) converts to an apparently spherical form, which may accumulate in the cytoplasm. As concentrations increase, spheres may join together to form potentially toxic chainlike protofibrils (bottom center). Chains can either fuse head-to-tail to produce annular protofibrils (bottom left) or side-to-side to produce the large fibrils that compose Lewy bodies (bottom right). One reason for the dearth of alternative Parkinson's therapies is the lack of a good understanding of its origins. It was only five years ago that researchers discovered that the gene for alpha-synuclein, the main constituent of Lewy bodies, was defective in people with early-onset forms of Parkinson's. The findings suggested that Lewy bodies might play a role in causing disease. But a mouse model of Parkinson's was bred that had high levels of alpha-synuclein deposits but no Lewy body-like fibrils. "It looked like you did not have to go all the way to a fibril to make things bad," Lansbury said. He and his colleagues had been working on Alzheimer's disease and had discovered that the amyloid protein passed through a protofibrillar stage on its way to forming amyloid fibrils. Suspecting that alpha-synuclein might be doing the same on its way to forming Lewy body-like fibrils, he and his colleagues set out to find an intermediate form, which they did last year. The Flies Have ItLansbury wanted to see if the Parkinson's protofibrils might be toxic, but he was stymied. The disease had been reproduced in mice, but conducting toxicity tests on the rodents would be laborious and time-consuming. Then in 2000, Feany reported that by expressing versions of the human alpha-synuclein gene, she had developed a strain of Parkinson's flies (see Focus, April 7, 2000). "The fact that flies get the disease totally changed my outlook," said Lansbury.In order to see if protofibrils cause disease in flies, Conway, Lansbury, and their colleagues had to find a way to keep the normally unstable protofibrils from converting to fibrils. They screened a small library of compounds in an effort to find one that would block the conversion. "When we started to look, it was obvious that something odd was happening," said Lansbury. The reagents that slowed conversion were all related to dopamine. "It was a complete surprise," he said. In addition to solving old puzzles, such as the disease's preference for dopaminergic cells, the findings explained another aspect of Parkinson's. For years, the disease had been thought to be a consequence of oxidative stress in the brain. Oxidative stress occurs when maverick electrons bombard and damage molecules inside cells. As it turns out, dopamine is extraordinarily vulnerable to oxidative damage. In fact, during their experiments, the researchers found that the protofibril-stabilizing dopamine was an oxidized form. Having discovered the affinity between oxidized dopamine and protofibrils in test tubes, Lansbury will be exploring the duo's effects in human postmortem tissue and a variety of animal models, including Feany's parkinsonian flies. He and Feany also plan to screen 900 Food and Drug Administration approved drugs to see if any might prevent the formation of protofibrils or degrade them and, if so, whether they prevent disease. If they do, a new therapeutic approach--one that combines dopamine replacement with drugs that prevent further degeneration--might be in the offing. "If one could stop the degeneration process at a point at which symptoms first become apparent, one could effectively treat Parkinson's symptoms indefinitely using known dopamine mimics," Lansbury said. --Misia Landau |
