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Fingering the Neural Perp in Parkinson's

New study finds it's not just dopamine-producing cells, but likely ones that secrete norepinephrine, as well, that kick-start the movement disorder
brain regions



© ISTOCKPHOTO/AARON KONDZIELA
Neuroscientists have long believed that the tremors, stiffness and sluggish gait characteristic of Parkinson's disease resulted from the death of neurons in a section of the midbrain that produce the neurotransmitter dopamine, which helps to maintain proper motion control.

A new study in mice, however, suggests that the disorder may actually be caused not only by hobbled dopamine-producing cells but also by neurons in the locus coeruleus region of the brain stem that produce norepinephrine, a chemical related to dopamine and associated with everything from anxiety to attention to blood pressure regulation. The new finding could lead to new therapies for combating the debilitating condition.

Researchers previously believed that Parkinson's, which affects an estimated 500,000 Americans, most over 60, was triggered when 80 percent of the dopamine-producing neurons in the substantia nigra region of the midbrain died, disrupting the signaling between that structure and another midbrain region called the striatum, which controls motion.

But David Weinshenker, an associate professor of human genetics at Emory University in Atlanta and senior author of the study published in Proceedings of the National Academy of Sciences USA, says autopsies on Parkinson's-ravaged brains showed a concurrent loss of norepinephrine-producing cells as well. "The death of norepinephrine neurons has been known among neuropathologists for decades," he says, yet the cells had not been linked to the causation of Parkinson's symptoms.

In mouse models of Parkinson's, middle-aged mice (typically one year old) are given a drug called MPTP (or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) that selectively kills their dopaminergic nerve cells. As a result, these mice show much of the same biochemical changes as humans suffering from Parkinson's, but do not display any of the motion problems. "We thought there must be a compensatory system out there somewhere that's kicking in," Weinshenker notes.

Weinshenker's team hypothesized that knocking out both norepinephrine-producing and dopamine-manufacturing cells would yield a model closer to the human illness that mimicked Parkinson's-like symptoms. They created a strain of genetically altered animals that could not produce the enzyme dopamine β-hydroxylase, the protein that converts dopamine into norepinephrine. Thus, these animals could produce dopamine, but could not make norepinephrine. The plan was then to selectively kill dopaminergic neurons with MPTP when the mice matured, effectively simulating Parkinson's.

But before they had a chance to dampen dopamine function, Weinshenker says, "to our surprise what we saw were Parkinsonian motor deficits." His team ran the animals through a battery of tests to analyze their gait, including their ability to walk a narrowing balance beam, descend a pole and run on a treadmill.

"They were impaired on every single test on our battery," Weinshenker notes, adding that some mice developed the hunched posture and tremors that human Parkinson's patients display. "A loss of 80 percent of their dopamine neurons is not enough to cause motor deficit, but loss of norepinephrine is."

Weinshenker says that the norepinephrine neurons actually modulate the dopamine release of the substantia nigra neurons. Without norepinephrine, dopaminergic cells can produce the neurotransmitter, but cannot release it—creating the Parkinsonian symptoms. When 80 percent of the dopamine cells are eradicated in mice, however, the brainstem cells can take over and instruct those remaining midbrain cells to make and release more of the motion-controlling chemical.

James Surmeier of Northwestern University's Feinberg School of Medicine in Chicago says the connection between Parkinson's and locus coeruleus neurons makes sense. "Locus coeruleus neurons are very similar electrophysiologically to substantia nigra dopamine-containing neurons," he says, in that they act as a pacemaker, setting the tone for the dopaminergic cells, which in turn modulate neurons in the striatum.

Weinshenker says that to improve the mouse model, he would consider breeding genetically normal mice and then selectively killing dopamine-producing cells with MPTP and norepinephrine-containing neurons with a drug called DSP4. That would likely produce a mouse that is both neurophysiologically and behaviorally similar to a human Parkinson's patient.

He adds that in terms of therapies for Parkinson's patients, "it might be worth treating the norepinephrine as well as the dopamine system," by supplementing the drug L-dopa, the current standard in care, with a tricyclic antidepressant, which is known to improve norepinephrine signaling.

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