Parkinson's Research Focuses on Links to Genes and Toxins

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Parkinson's Research Focuses on Links to Genes and Toxins

By Linda Carroll, the New York Times

February 10, 2004

Parkinson's disease has baffled scientists ever since it was identified in the early 1800's. Although some evidence suggested that genes might have a role in causing the disease, for the most part old age was the sole characteristic that patients seemed to have in common.

But in the last 20 years, with the discovery that both chemical toxins and genetic mutations can lead to similar disorders, scientists are beginning to unravel the process that leads to the death of brain cells and, ultimately, rigidity, tremors and other symptoms of Parkinson's.

"What we have learned in the last five years is just breathtaking," said Dr. Howard J. Federoff, a professor of neurology who is the director of the Center for Aging and Developmental Biology at the University of Rochester. "And my guess is that the pace will continue to accelerate."

Many scientists now suspect that a vast majority of Parkinson's cases are caused by interplay between an inherited genetic susceptibility and environmental toxins. But many of the insights have come from research into rare inherited forms of the disease.

"All of these rare genetic forms of Parkinson's disease are giving us clues about a common pathway," Dr. Peter T. Lansbury, an associate professor of neurology at Harvard, said. "If you interfere with that pathway in a big way — by a mutation, for example — then you're guaranteed to get Parkinson's. But if it's in a subtle way, you only increase a person's risk of developing the disease."

More than 500,000 Americans live with Parkinson's, according to the National Institutes of Health. Each year, 50,000 new cases are diagnosed. Medications can treat the symptoms, but none have been shown to slow the progression of the disease.

In 1960, researchers discovered that Parkinson's symptoms were caused by the loss of the neurotransmitter dopamine through the deterioration of the substantia nigra, a small black oblong group of cells at the base of the brain. "Dopamine is like the oil in the engine of a car," Dr. Clive N. Svendsen, a professor of anatomy and neurology at the Waisman Center of the University of Wisconsin, said. "If the oil is there, the car runs smoothly. If not, it seizes up."

For years, scientists could not figure out why the cells were being damaged and dying. In 1982, researchers stumbled across a chemical, MPTP, that seemed to produce Parkinson's-like symptoms overnight. The chemical, a contaminant in some batches of heroin, left drug users rigid and slow.

They had difficulty speaking and a shuffling gait, said Dr. J. William Langston, scientific director and chief executive of the Parkinson's Institute in Sunnyvale, Calif., who first linked MPTP with Parkinson's. "They had all the features of advanced Parkinson's," he added.

By linking MPTP to Parkinson's, researchers had the first inkling of what might be killing dopamine cells. MPTP is highly toxic to tiny crystalline structures, the mitochondria, which are the cells' power plants.

When the mitochondria fail, Dr. Langston said, "it's like a blackout."
"There's no power to run the cell," he said.
Worse yet, when the mitochondria start to malfunction, they spew out toxic oxygen free radicals. That "causes much greater harm than the blackout," Dr. Langston said. The free radicals can corrode proteins in the cell and damage DNA.

Once the link with mitochondrial damage had been found, the researchers began looking at chemicals with similar effects like the pesticide rotenone and the herbicide paraquat.
Other researchers identified several Parkinson's genes. At least two appear to affect protein management. One is involved in creating a protein called alpha-synuclein; the other in tidying up excess or damaged copies of proteins. Scientists do not know exactly what alpha-synuclein does when it functions properly. But they are starting to understand what happens when the protein malfunctions.

Mutations of the gene that encodes for alpha-synuclein appear to lead to misfolding of the protein, said Dr. John Q. Trojanowski, the director of the Institute on Aging and a professor of geriatric medicine, at the University of Pennsylvania. When a protein misfolds, it becomes useless and hard to dispose of, he said, comparing it to a piece of paper. "When it's scrunched up, it's not useful for reading or writing. Its function is lost. The same is true of proteins."

Further, misfolded proteins do not fit well into the cell's trash-disposal system, Dr. Trojanowski added. "The disposal system becomes impaired and overwhelmed," he said. "And suddenly, there's a lot of protein sludge clogging up the nerve cells."

Mutations of the alpha-synuclein gene also appear to cause bits of the protein to clump together. "In the test tube, two mutant forms cause synuclein to aggregate more rapidly," Dr. Lansbury said, adding that if the synuclein is increased, it aggregates faster. Clumped proteins may lead to cell death because these globs are hard to dispose of.

Dr. C. Warren Olanow, chairman of neurology at Mount Sinai School of Medicine in New York, described it this way: "If you think of a garbage disposal in your sink, imagine a great big lump of something that just won't fit into it, even though the component parts would."

A study in the journal Science in October also suggested problems with alpha-synuclein by showing that Parkinson's could result when a person had three normal copies of the gene that produces the protein. So even if the protein is normal, too much can cause disease, Dr. Trojanowski said.
In autopsy studies in the early 1900's, researchers found that nerve cells from Parkinson's patients tended to be marked by little blobs of protein. The researchers suspected that the blobs, called Lewy bodies, might be killing the cells.

But with the discovery six years ago that Lewy bodies were crammed with alpha-synuclein, scientists now think that the blobs are formed when cells try to protect themselves by corralling broken copies of alpha-synuclein that do not fit in the disposal.
Ultimately, though, that strategy may kill the cell. "Imagine that you can no longer take any of your garbage out of the house," Dr. Langston of the Parkinson's Institute said. "Pretty soon, your house will become uninhabitable."

In the last several years, scientists have learned that when some animals are exposed to certain toxins, a Parkinson's-like disorder results. When rats experience low levels of rotenone, some become slow and stiff like Parkinson's patients, said Dr. J. Timothy Greenamyre, a professor of neurology and pharmacology at Emory University. "When their brains are examined, they have a loss of the same dopamine neurons that degenerate in Parkinson's disease.

These rats also develop structures that look very similar to the Lewy bodies in Parkinson's patients, Dr. Greenamyre said.
A study published in November showed that rotenone wreaked its damage through oxygen free radicals.

The rotenone-rat studies also point to a connection between genes and the environment. Not all rats, even inbred ones, are equally susceptible to rotenone, said Dr. M. Flint Beal, chairman of the department of neurology and neuroscience at the Weill Medical College of Cornell University.

"At the same dose, there's marked variation in the severity of its effects," Dr. Beal said. "The rats are inbred. So they should be pretty darned close. But they're not perfectly identical."
Dr. Beal suspects that some rats may have inherited mitochondria that are better at resisting the damage from rotenone.

As researchers learn more about genes and toxins, they are starting to see a convergence in a common path to dopamine cell death. A 2002 study published in The Proceedings of the National Academy of Sciences found that mice were protected from the effects of MPTP if they had no alpha-synuclein genes.
As it turns out, damage by toxins to alpha-synuclein looks quite similar to what results from certain genetic mutations.

"Oxygen free radicals can cause two different parts of a single protein to become cross-linked, so that it can't assume its proper shape, which is similar to what happens with a genetic mutation," Dr. Greenamyre said.
"A rough analogy is putting handcuffs on a person so their arms can't function properly," he added.
Free radicals can also make proteins sticky, so that they clump together, Dr. Greenamyre said. "That would be like handcuffing more than one person together," he added.

Studies have also shown that free radicals can damage cells' disposal system, Dr. Greenamyre said. "So, oxidative damage can produce both too much damaged misshapen protein and, also simultaneously, damage the system that normally clears the damaged proteins from the cell."

Another bit of information linking genetic and environmental causes is that researchers have found that too much alpha-synuclein can lead to oxidative damage.
Scientists have not worked out every detail of the cascade of events that leads from nerve cells' initial injury to demise. More genes may be found.

More toxic substances that can damage nerve cells may turn up as researchers focus on Parkinson's patients, looking at exposure to chemicals known to generate free radicals or damage mitochondria. "This is the link between basic research and actual patient populations," Dr. Langston said.
Though none of the new research points to a clear road to a cure, said Dr. Federoff of the University of Rochester, understanding the basics of neuron death may pay off with better treatments.

"Do I think there will be a cure in the next 5 to 10 years?" he asked. "No. But I believe that we will have strategies that will slow the progression of the disease. And for afflicted individuals, there will be a better quality of life."