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Discovery Offers New Insight Into Parkinson's

Biologists say they have gained a new insight into the basic cause of Parkinson's disease that, if confirmed, could lead to a novel class of drugs.

The cause of the disease appears to lie in the nerve cell's internal delivery system for shuttling packets of chemicals around, a team of researchers led by Susan Lindquist of the Whitehead Institute in Cambridge, Mass., report in today's issue of Science.

Tremors and other symptoms of Parkinson's result from the death of certain neurons. Another sign of the disease is the appearance inside these neurons of clumps of protein known as Lewy bodies.

Many experts believe the clumps are toxic to the neurons. But the reason for the clumps is obscure, as is the presence in them of large amounts of a mysterious protein known as alpha synuclein.

Dr. Lindquist and her colleagues believe they have come close to defining the normal role of this protein. It appears to be involved in the elaborate system by which packets of chemicals are transferred between compartments within the cell, and may accumulate in human cells because of a breakdown in this rapid and tightly controlled traffic, she believes. She has also been able to reverse the damage, at least in laboratory organisms, by inserting genes that counteract synuclein.

Ted Dawson, an expert on Parkinson's disease at Johns Hopkins University, said the new finding could have a major impact on research.

"The hope would be that from this new knowledge we could develop new therapies that could treat Parkinson's disease," he said.

A surprising aspect of the discovery is that it was made first not in a complex organism, but in yeast, a single-celled fungus that has no hint of a nervous system. Though many researchers have assumed the cause of Parkinson's is specific to the special nerve cells that are lost in the disease, Dr. Lindquist believed that some basic cellular process might be to blame, in which case it could best be explored first in yeast, a well-studied organism that is easy to manipulate in the lab.

Dr. Lindquist and her colleagues genetically engineered a strain of yeast that produced somewhat more synuclein than is normal, which made the cells sickly but did not kill them. She then exposed this strain to extra copies of 3,000 yeast genes, finding some genes that helped the cells and some that made them worse.

Both sets of genes were of types known to be involved in the cell's packet delivery system, suggesting that synuclein was part of the same process.

While this seemed to be an advance in understanding synuclein's natural role, many were doubtful that a finding in yeast could have any significant bearing on what happens in human brain cells or Parkinson's disease.

Dr. Lindquist extended her finding to organisms with nervous systems, including those whose neurons produce the nerve-to-nerve-signaling chemical called dopamine. Dopamine-producing neurons are the ones chiefly affected in Parkinson's.

One of the genes that cured the yeast cells of producing too much synuclein is involved in accepting delivery of packets intended for the Golgi apparatus, a compartment where the cell sorts and processes packets of chemicals. Dr. Lindquist's lab asked colleagues who work with roundworms, fruit flies and rats to see if this packet-accepting gene would rescue the dopamine-producing neurons in these animals from the effects of too much synuclein. In all cases it did, the researchers say in their report.

But if synuclein is involved in a basic cellular process like the packet delivery system, why should its toxic side effects only turn up in the dopamine-producing neurons of the brain? Dr. Lindquist believes the neurons have to last a lifetime, not being renewable like most other types of cells in the body, and that dopamine is easily converted into chemicals that damage the cell's proteins.

Dopamine transmits signals from one neuron to another, and packets of the chemical are processed in a cycle lasting about one-thousandth of a second. If the trafficking system were even slightly slowed for some reason, perhaps due to the age of the cells, there might be a delay in inserting dopamine into protective packets, allowing it to accumulate free in the cell and damage many proteins, Dr. Lindquist suggested.

Dr. Dawson, of Johns Hopkins, said there had been some previous hints that synuclein might be involved in the cell's trafficking system but that Dr. Lindquist's group had provided "some really convincing data."

But some cell biologists may need more convincing. Thomas Sudhof, of the University of Texas Southwestern Medical Center, has produced mice that lack the synuclein gene altogether yet seem normal, suggesting the protein does not play a vital role in cell trafficking.

Source Date: Jun 23 2006
Source Publication: The New York Times
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