Rethinking Dopamine's Role in Parkinson's Disease

February 12, 2008

It is widely agreed that the disorder, which kills certain dopamine-producing cells, can result from an imbalance between toxic and protective mechanisms within those cells.  Some researchers continue to focus on dopamine itself as a possible factor in triggering this fatal imbalance.

For more than four decades, the muscular rigidity and tremor that are the classic signs of Parkinson’s disease have been blamed on the lack of the neurotransmitter dopamine in one of the key movement-controlling regions of the brain.  For almost as long, the mainstay of Parkinson’s therapy has been to replace dopamine in the brain, using the drug Levodopa.

In recent years, however, some researchers have wondered whether dopamine may actually be helping to cause the disease.

The idea has been much-disputed, and a major issue has been whether dopamine-replacement with Levodopa might be doing more harm than good. “The outcome on clinical studies looking at that question is still somewhat controversial,” says neurologist Bruce Yankner, a researcher at Harvard.

So far there is no good evidence that Levodopa does hasten the underlying disease process, and patients who take the drug should not be alarmed. But some researchers continue to investigate whether the brain’s own production of dopamine, within the very cells that are killed in the disease, may be part of the reason those cells are dying.

Dopamine: Handle With Care

It has long been known that when dopamine is broken down inside the brain cells that produce it, oxygen free-radicals and other potentially damaging molecules are produced.  “Those dopamine neurons seem to be very vulnerable in the disease,” notes Gary Miller, a Parkinson’s researcher at Emory University.  “And that oxidative environment, with dopamine being there, does seem to suggest a connection to dopamine itself.”

The dopamine supply that dries up in Parkinson’s comes normally from a dark-pigmented pool of neurons known as the substantia nigra. Through the tendrils of dopamine-producing nigral cells, the neurotransmitter flows downstream to another region known as the striatum, stimulating neurons that exert a basic control over muscles. In Parkinson’s disease, this dopamine flow slows because most of the nigral cells producing it die–and no one knows why.

It is widely agreed that “oxidative stress,” caused by an unmanageable level of cell-damaging free-radicals, is at least partly responsible for the deaths of nigral cells. There is strong evidence, too, for the involvement of a protein known as alpha-synuclein, mutations of which are known to cause rare inherited forms of Parkinson’s, and mysterious clumps of which are often found in dying nigral cells.

How these two processes interact in the majority of Parkinson’s cases is still a mystery. But Miller and his colleagues recently showed that dopamine itself could lead to oxidative stress in nigral cells, and also could lead to alpha-synuclein accumulation.

Miller’s group genetically engineered mice to produce abnormally low amounts of VMAT2, a protein that usually packages nearly all dopamine in nigral cells safely into “vesicles,” for transport out of the cells. Without the ability to pack dopamine safely away, the nigral cells in the mice showed signs of oxidative stress, and as the mice aged, they began to show Parkinson’s-like symptoms. Miller’s group also found clumps of alpha-synuclein in the withered and dying cells.

Other researchers have been reporting evidence of dopamine’s toxic potential. In January 2008, a group at the University of Chicago reported having genetically engineered the striatal neurons of mice, which absorb but don’t produce dopamine, to soak up an abnormally large amount of the neurotransmitter from nigral neurons supplying it. The dopamine-stuffed striatal cells soon withered and died, showing markers of oxidative stress, although they became healthier when their supply of dopamine was cut off.

Also in January, collaborating researchers from the Albert Einstein College of Medicine, Harvard, and other institutions reported that dopamine can modify alpha-synuclein into a form that blocks a key cleanup mechanism within cell—thus potentially allowing an assortment of unwanted, toxic molecules to accumulate.

The idea suggested by these results is that almost any significant impairment of the usual safe-handling mechanisms for dopamine could trigger disease. “If the protective mechanisms are compromised,” says Xiaoxi Zhuang, one of the Chicago researchers, “whether by genetic mutation, or aging, or toxins in the environment, or for a combination of reasons, the small extra amount of dopamine could become devastating.” More dopamine could mean more damage to the cell, more impairment of other cleanup mechanisms, and so on in a vicious spiral. Zhuang points out that mutations in the parkin and DJ-1 genes, which cause rare, familial forms of Parkinson’s disease, are known to impair two of the basic protective mechanisms within brain cells.

But hold on, says Gene Johnson, a professor of neurology at Washington University who also chairs the advisory board for the Michael J. Fox Foundation. “Everybody tends to focus on dopamine neurons but there are other neurons affected in the disease that perhaps degenerate even earlier than dopamine neurons.”

Mark Cookson, a specialist on Parkinson’s genetics at the National Institute on Aging, agrees. “A large number of Parkinson’s patients get dementia and other symptoms that are unrelated to dopamine,” he says. “So dopamine can’t be the whole answer to Parkinson’s.”

But even the researchers who have been studying dopamine’s toxicity don’t see it as the end of the story. “Dopamine is just one of the many factors that can contribute to cellular stress,” says Zhuang.

Gary Miller, for his part, thinks that the mishandling of dopamine by nigral cells might be only the most prominent example of a degenerative process at work throughout the brain. “What we saw in our research with dopamine might be occurring in other systems,” he says, “because norepinephrine and serotonin have similar vesicular storage mechanisms. Actually they’re all stored by VMAT2 the same way. And so we think that the mishandling of all these neurotransmitters might be contributing to this disease.”

Miller points out that norepinephrine chemically is a particularly close cousin to dopamine. “And the neurons that make norepinephrine in the locus ceruleus,” another brain region, “also degenerate in Parkinson’s. Not quite to the extent of the dopamine neurons, but they do.”

Miller suspects that neurotransmitters, such as dopamine, that have relatively toxic breakdown products are more likely to damage the brain cells that produce them. If further research proves this true, says Miller, it could explain the essential mystery of Parkinson’s—namely, “why some brain regions have more problems than others.”

But Miller emphasizes, “We’ve still got a lot of work to do.”

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