Download Worms hold clues to Parkinson`s disease, drug abuse

Worms hold clues to Parkinson’s disease, drug abuse
By Leigh MacMillan
March 11, 2002
Could a lowly worm offer new insights to a disease as complex as Parkinson’s?
Investigators in Vanderbilt’s 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 Parkinson’s 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 Parkinson’s patients with shaking limbs,
uncoordinated movements, and shuffling gaits. No one knows why these neurons die.
Even though worms don’t get Parkinson’s disease, they do have dopamine neurons,
eight of them to be exact. And they’re remarkably similar to the ones in the human brain. “Every
building block we know that’s involved in making a dopamine neuron in human beings is present
in the worm dopamine neurons,” says neuroscientist Randy Blakely. 1
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.
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.
They cloned the C. elegans dopamine transporter (CeDAT). Then, using techniques
standard to the worm field, they genetically engineered worms to make a fluorescent protein in
the neurons that contain CeDAT, allowing them to actually “look” at these neurons in living
worms. “This was the first time that anyone’s ever been able to see dopamine neurons in a living
animal,” says an enthusiastic Nass.
Here’s where the Parkinson’s 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 toxin’s effects. And these discoveries could in turn suggest ways to protect dopamine neurons
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 Parkinson’s disease, drug abuse
from the cell death – possibly triggered by an environmental or endogenous toxin – that occurs in
Parkinson’s 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 “see” the dopamine neurons and
work with them in isolation, Blakely says, they can learn new things “about how the dopamine
transporter works in bona fide dopamine neurons.”
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 “to foster highly innovative or conceptually creative research that advances our
understanding of drug abuse and addiction and how to prevent and treat them.”
Blakely acknowledges that the worm is not a model for drug abuse or addiction. “But it’s 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.
“The worm dopamine transporter is the same molecule as the mammalian version. Sure,
it’s separated by a few million years of evolution,” he says, grinning, “but it’s genetically related
and has the same structural properties. We believe this model will really advance our basic
understanding of dopamine transporter function.”
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