JANUARY 22, 2001 VOL. 157 NO. 3

The Hunt for Cures

Parkinson's Disease
Lubricating gummed-up brains
By JEFFREY KLUGER

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It's hard to imagine asking a doctor to destroy a part of your brain. For the millions of people suffering from Parkinson's disease, however, such a drastic measure—in which an electrode is used to kill tremor-causing neurons—may become necessary.

The irreversible procedure is just one of many therapies, both surgical and pharmacological, that Parkinson's patients have tried over the years to control the tremors, rigidity and other symptoms that characterize the disease. All the treatments offer some relief, but none can remotely be called a cure. Now that may be changing. The further scientists peer into the human genome, the more they are uncovering the secrets of Parkinson's—and the more they are becoming convinced that next-generation drugs may at last be able to beat back the disease. What's more, the benefits may not be limited to Parkinson's but may also be used to treat Huntington's, Lou Gehrig's and even Alzheimer's disease—all of which have similar neurodegenerative roots and may respond to similar drugs. Says neurobiologist Michael Zigmond of the University of Pittsburgh: "A breakthrough in any of these diseases could have an impact on the others."

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The first place to look for causes of and treatments for Parkinson's disease is in the brains of patients. As the illness worsens, brain tissue becomes clogged with a protein muck that includes a substance called alpha-synuclein. No one knows exactly what alpha-synuclein does, but it's believed to play a role in the smooth transmission of nerve signals. When the substance clumps, it can't do the work it was designed to do, leading to neuron damage, loss of the neurotransmitter dopamine and eventually the familiar shakiness of such well-known Parkinson's sufferers as Janet Reno and Muhammad Ali.

The hunt for a Parkinson's cure got a boost in 1997 when researchers discovered a handful of patients whose alpha-synuclein genes had mutated. This might seem like open-and-shut evidence that the cause of the illness had been found, except that the vast majority of Parkinson's patients, whose brains also grow gummed up, do not carry the mutation. Still, scientists believe that the bad gene is a powerful clue. "There appear to be more clumps in the brains of people with the mutant gene," says Zigmond. "Learning how the protein functions may help us develop drugs that target it."

Another gene, newly dubbed the parkin gene, has also been getting a lot of attention. In 1998 Japanese researchers reported on studies conducted on five young patients with early-onset Parkinson's, all of whom carried a recessive gene that appeared to be associated with the disease. Though relatively rare, the parkin gene is much more common than the defective alpha-synuclein gene, and in places like China, with high rates of early-onset Parkinson's, it may play a role in a significant number of cases. Just last October, researchers at Duke University Medical Center went a step further, reporting their discovery of a previously unseen mutation on the parkin gene that appears to link it to late-onset forms of the disease as well. "Once we figure out how that gene functions," says neurology professor Ira Shoulson of the University of Rochester Medical Center, "we could perhaps disrupt it pharmacologically."

Just as important as protecting healthy neurons is repairing or replacing nerve cells that have been damaged. The body produces a whole bath of trophic—or growth—factors that help cells develop. If the brains of Parkinson's patients could be fortified with additional trophic doses, many scientists believe, damaged neurons might be reawakened or repaired. While there is some thought in the medical community about engineering genes to churn out the substances, the pharmaceutical industry is taking a more direct approach.

Currently, American firms Guilford Pharmaceuticals in Baltimore and Amgen in Thousand Oaks are collaborating on a synthetic neurotrophic compound that can be taken orally and then travels to the brain, where it bonds with proteins in dopamine neurons. The tricky part is that most trophic molecules are too big to move across the miniscule blood vessels in the brain, so Guilford and Amgen are working on a smaller one that can get where it needs to go. The progress so far is promising. "We're in Phase 2 human trials now," says Dr. Craig Smith, president of Guilford. "Although we don't have results yet, if the drug proves safe and extremely effective in trials, it could be on the market as early as 2005."

Whether such an anti-Parkinson's potion is really so close at hand is unclear, but scientists are not waiting to find out. Other possible treatments under study include boosting antioxidants, which would protect brain cells from free radicals, highly reactive molecules that are by-products of oxidation; and blocking the body's production of compounds called excitatory amino acids, which can cause neuron damage. It's hard to say which, if any, of these treatments will succeed, but with science closing in from so many directions, it's possible that for the first time, Parkinson's disease may find itself on the run.

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