clues to Parkinsonís disease, drug abuse
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.
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.
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
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.
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
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
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
Blakely information and research description
Blakely Lab home page