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Dopamine May Play Dual Role in Parkinson's Disease
A 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.
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).
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.
Lansbury says the preliminary findings are consistent with this hypothesis that protofibrils are to blame in Parkinson's. "It's the earliest things that are the problem," he said.
Copyright 2001 by the President and Fellows of Harvard College