Dopamine May Exacerbate Parkinson's Disease

Misfolding. Dopamine may keep toxic protofibrils in place (top) by preventing them from forming fibrils (bottom).

The tremors, stiffness, and slurred speech that accompany Parkinson's disease are rooted in the death of neurons that churn out dopamine, a chemical that controls muscle movement. But precisely what kills these brain cells has long stumped researchers. Now a provocative study suggests that a surprising culprit--a form of dopamine itself--may assist in the neurodegeneration that defines the disease.

Neurons in parts of the brain stricken by Parkinson's disease are marked by tangled deposits called Lewy bodies. These clumps are made of the folded, or fibrillar, version of a protein called a-synuclein. Neuroscientists initially assumed that fibrillar a-synuclein--as opposed to the unfolded form common in healthy brains--is responsible for neural demise. Recently, however, researchers have pursued a version of a-synuclein that hovers between normal and fibrillar, called protofibrillar, which some consider far more toxic than the fibrillar form.

To better understand protofibrils, Peter Lansbury of Harvard Medical School in Boston and his colleagues searched for compounds that affect protofibril formation. As the team reports in the 9 November issue of Science , of the 169 compounds screened, 15 inhibited the transition from protofibril to fibril--a bad thing if protofibrils are toxic, as the group believes--in a test tube containing a-synuclein . Fourteen of these belonged to a set of neuromodulators called catecholamines, which includes dopamine. Because Parkinson's disease is caused by a loss of dopamine, it seemed odd that dopamine and dopamine-like compounds could worsen the disease.

When the team added antioxidants to the test tube mix, the transformation of protofibrils to fibrils sped up again, providing a key clue. Dopamine is formed in the cytoplasm, where it can be oxidized, Lansbury explains. But the dopamine that goes to the synaptic vesicles, where it's stored and released, is protected from oxidation. Lansbury speculates that the natural balance between dopamine and its oxidized form goes awry in Parkinson's patients.

Virginia Lee, a neurobiologist at the University of Pennsylvania in Philadelphia, says the work complements mounting evidence that protofibrils are harmful and that oxidative stress helps them stick around. But scientists agree that the study should be repeated in cell cultures and laboratory animals so the results can be reaffirmed and better understood.

Related sites

Peter Lansbury's research
Virginia Lee's research
Parkinson's Disease Research Web from NIH
Parkinson's Disease Foundation

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