Footnote #1
Director of the Center for Molecular Neuroscience, Allan D. Bass Professor of Pharmacology, Kennedy Center investigator and senior fellow.

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Worms hold clues to Parkinsonís disease, drug abuse

By Leigh MacMillan
March 11, 2002

Could a lowly worm offer new insights to a disease as complex as Parkinsonís? Investigators in Vanderbiltís Center for Molecular Neuroscience believe so. They have turned to the worm C. elegans to study the death of dopamine neurons - the same type of nerve cells that die in humans suffering from Parkinsonís disease.

Dopamine neurons - nerve cells that use the chemical neurotransmitter dopamine to communicate with other nerve cells - populate regions of the human brain responsible for movement. The death of these neurons leaves Parkinsonís patients with shaking limbs, uncoordinated movements, and shuffling gaits. No one knows why these neurons die.

Even though worms donít get Parkinsonís disease, they do have dopamine neurons, eight of them to be exact. And theyíre remarkably similar to the ones in the human brain. ďEvery building block we know thatís involved in making a dopamine neuron in human beings is present in the worm dopamine neurons,Ē says neuroscientist Randy Blakely. Click to open footnote, then click again to close

One of those building blocks is a protein called a dopamine transporter. Transporter proteins act as miniature vacuum cleaners - after a neuron has dumped neurotransmitter into the synapse, transporters spring into action to sweep it back inside. They are key to the complex chemical signaling in the nervous system.

Neurostransmitter Transportation AnimationNeurostransmitter Transportation Animation

Blakely and others have identified and characterized a whole family of transporters, discovering along the way that these proteins are targets for both therapeutic drugs and drugs of abuse. The newest antidepressants for example, including Prozac, work by blocking the transporter protein for the neurotransmitter serotonin. Amphetamines and cocaine affect the function of transporters for several different neurotransmitters.

The complexity of the mammalian nervous system makes it nearly impossible to study the function of a single type of molecule, like a transporter, in the living animal. Blakely and postdoctoral fellow Richard Nass recognized the advantages of the worm - its short life cycle, its simple and fully characterized nervous system, its sequenced genome - for advancing their studies of transporter function.

Blakely collaborated with David Miller's group to establish a worm program in his lab, previously dedicated to mammalian neurobiology, and to clone the C. elegans dopamine transporter (CeDAT). Next, using techniques standard to the worm field, Nass genetically engineered some worms so that the neurons that contain CeDAT are labeled with fluorescent protein, allowing them to actually "look" at the neurons in living worms. "This was the first time that anyone's ever been able to see dopamine neurons in a living animal," Nass enthuses.

Hereís where the Parkinsonís disease connection comes in. The investigators know that they can selectively kill the dopamine neurons - they can apply a toxin and simply watch the fluorescent cells die. Now they will make genetic mutations and look for worms whose dopamine neurons do not die when they are exposed to the toxin.

The studies could point to genes and biochemical pathways that are protective against the toxinís effects. And these discoveries could in turn suggest ways to protect dopamine neurons from the cell death - possibly triggered by an environmental or endogenous toxin - that occurs in Parkinsonís disease, Blakely says.

Blakely and Nass believe their novel worm model will also offer new information relevant to drug abuse. The dopamine transporter is a protein target for drugs of abuse including amphetamines and cocaine. Because the investigators can ďseeĒ the dopamine neurons and work with them in isolation, Blakely says, they can learn new things ďabout how the dopamine transporter works in bona fide dopamine neurons.Ē Paul MacDonald, a graduate student in the lab, is developing mass spectrometry-based approaches to identify novel proteins that control the dopamine transporter and could be new targets for drug development.

The studies are being funded by the National Institute on Drug Abuse through a program called CEBRA: Cutting-Edge Basic Research Awards. NIDA introduced the CEBRA grants this year ďto foster highly innovative or conceptually creative research that advances our understanding of drug abuse and addiction and how to prevent and treat them.Ē

Blakely acknowledges that the worm is not a model for drug abuse or addiction. ďBut itís a great model for getting fundamental information about the dopamine transporter - a molecule whose function we know to be important for drug action in the mammalian brain, but which we have limited opportunities to study there.

ďThe worm dopamine transporter is the same molecule as the mammalian version. Sure, itís separated by a few million years of evolution,Ē he says, grinning, ďbut itís genetically related and has the same structural properties. We believe this model will really advance our basic understanding of dopamine transporter function.Ē

Randy Blakely information and research description

The Blakely Lab home page

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