News Column

Penn Unlocks a Parkinson's Puzzle Piece

Nov. 16, 2012

Tom Avril

Parkinson's disease appears to spread through the brain by means of a simple yet insidious mechanism, according to research to be published Friday by University of Pennsylvania scientists.

When molecules of a certain protein become corrupted in the brain, they can pass on their distorted shape to healthy proteins through nothing more than physical contact.

Like something out of a bad science-fiction movie, more healthy proteins latch onto the ones that have gone bad, adopting their "misfolded" configuration until deadly clumps build up in brain cell after brain cell, the Penn team found in its study of lab mice.

These clumps, known as Lewy bodies, were discovered long ago, but the authors -- led by the prominent neurobiologist Virginia M.-Y. Lee -- say they now have hard evidence that the clumps play some sort of causal role in the disease.

What's more, the researchers are optimistic they can stop it in its tracks, because the bad proteins may be vulnerable as they travel from one cell to the next.

Scientists have suspected for years that a number of brain diseases follow this infectious-like path. But experts not involved with the new paper say it makes an especially strong case -- at least with Parkinson's, which kills more than 20,000 people in the United States each year.

"This is, as far as I'm concerned, the most convincing evidence thus far that supports this hypothesis," said Robert Edwards, a professor of neurology at the University of California, San Francisco.

J. Paul Taylor, who studies brain diseases at St. Jude Children's Research Hospital in Tennessee, agreed with the Penn team that stopping the spread of the bad proteins seemed feasible, perhaps with a specially tailored antibody.

Indeed, Lee, who directs the Center for Neurodegenerative Disease Research at Penn's Perelman School of Medicine, said she and her colleagues are testing that idea in mice.

"We can catch the bad proteins as they go from one neuron to another," Lee said.

She cautioned that while the bad proteins seem to have an infectious quality within the brain, there is no evidence that Parkinson's can be passed from person to person.

Lee's chief collaborator on the paper was Kelvin C. Luk, who was recently promoted to research assistant professor at Penn.

Also on the team was Lee's husband, John Q. Trojanowski. The pair are internationally known for a series of discoveries on Parkinson's, Alzheimer's, and Lou Gehrig's diseases -- any one of which would be a career-defining highlight for most scientists.

On Friday, the same day the new paper comes out, Lee and Trojanowski are receiving the John Scott Award, a science prize administered by the Board of Directors of City Trusts. They will be recognized in an evening ceremony at the American Philosophical Society, along with Princeton University physicist Paul J. Steinhardt.

Though there are drugs to ease the tremors and other symptoms of Parkinson's, it and the other neurodegenerative diseases have resisted efforts at a cure. That is partly because scientists have had trouble reproducing the diseases in lab animals, making it hard to test new drugs.

In the case of Parkinson's, for example, scientists have made mice with Lewy bodies, and they also have made mice with the other primary sign of the disease -- the loss of neurons that produce the vital brain chemical called dopamine. But they have been unable to make a mouse that develops both flaws -- until now, in the new research from Penn.

Once the mice were injected with a small sample of the corrupted proteins, called alpha-synuclein, they went on to develop Lewy bodies and their dopamine-producing neurons started to die. Also, they lost muscle strength and coordination, much like their human counterparts.

Still unknown is the process by which the proteins start to go bad, but once they do, a deadly cascade ensues, said Luk, the first author of the paper.

He said the reason the corrupted proteins can pass on their misfolded shape, apparently, is because healthy proteins are relatively flexible, whereas the distorted ones have a stable configuration.

"It actually somehow nudges the flexible, normal protein into adopting the same kind of shape," Luk said. "It's templating it, almost."

The Penn team previously observed this templating process in a test tube, but only now have shown that the spreading can occur in a brain.

Another possible explanation had been that the disease was triggered independently in many brain cells, due to some underlying problem.

But in the mice at Penn, the spread of disease was initiated with the injection of the bad proteins in just one region of the brain, the striatum.

Clumps of bad proteins eventually showed up in other brain regions that are connected to the striatum, including the amygdala and the substantia nigra -- the home of the cells that produce dopamine.

Within three months, about 15 percent of those cells had died. By six months, half of them were dead.

Lewy bodies are named for Friedrich Lewy, who discovered the protein clumps in Germany in 1912. Amid the rise of the Nazis, Lewy fled to England and moved to Philadelphia in 1934, where he later joined the Haverford Quaker community.

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Source: (c) 2012 The Philadelphia Inquirer