Jun 23, 2006    #103
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Researchers reverse Parkinson's symptoms in animal models Breakthrough in Parkinson's studies to be published in Science

More than a million Americans suffer from Parkinson's disease alone — a number that is expected to soar over the next few decades as the population ages. No current therapies alter the fundamental clinical course of the condition.

Now, scientists at the University of Missouri-Kansas City (UMKC) School of Biological Sciences, in collaboration with colleagues at several research centers, including the Whitehead Institute of Biomedical Research in Cambridge, Mass., have identified a key biological pathway within neuron cells that, when obstructed, causes Parkinson's symptoms. Even more importantly, they have discovered how to repair that pathway and restore normal neurological function in animal models. Researchers have seen Parkinson's disease symptoms eliminated in the fruit fly, C. elegans (worm), and in rat neurons.

“This gives a whole new direction in the study of degenerative disorders like Parkinson’s,” said UMKC’s Antony Cooper, Ph.D., a senior author on the paper which has been accepted for publication by Science. “It may help in the development of much better treatment strategies and perhaps better drug therapies for Parkinson’s patients.”

The paper, which may be viewed in advance at Science Express online, reported that when a Parkinson's-related protein called alpha-synuclein was over-expressed in these cells, clumps of misshapen proteins gathered near the membrane, and in many cases the cells either became sick or died.

Scientists at the Harvard Institute of Proteomics prepared an array of individual yeast genes capable of being over-expressed in cells. The research group at the Whitehead Institute, led by Susan Lindquist who is also a senior author on the paper, introduced the genes into cells that were also expressing lethal levels of alpha-synuclein. They reasoned that if they identified genes whose over-expression rescued a cell, that would tell them something about how alpha-synuclein made the cell sick in the first place.

Most of the proteins that they identified pointed to a pathway that involves two cellular organelles, the endoplasmic reticulum (ER) and the Golgi. The ER is the cell's factory for proteins destined for export. Once a protein has properly folded in the ER, it is trafficked over to the Golgi, where it is fine-tuned and further prepared for its designated task.

Working together, research teams in Cooper’s and Lindquist’s laboratories demonstrated that when alpha-synuclein becomes mutated and clumps at the cell surface, it manages to drag away a protein called Ypt1/Rab1 that helps transport between the ER and the Golgi. Proteins are blocked from navigating this crucial route, and the cell dies. The misfolding and clumping of alpha-synuclein is specifically associated with Parkinson's Disease. Increasing the expression of Ypt1/Rab1 in yeast saved the cells from dying.

After the study on yeast, the next goal was to find out how the findings translated with actual neurons. Could cell death be averted simply by increasing the levels of transport protein Ypt1/Rab1? Working with colleagues at University of Pennsylvania, University of Alabama, and Purdue University, the consortium tested the hypothesis in the fruit fly, C. elegans (worm), and in neurons culled from rats — all of which had alpha-synuclein-induced Parkinson's symptoms. In every case, symptoms were reversed by increasing levels of Ypt1/Rab1.

The work was supported by the National Institutes of Health.

UMKC is one of four University of Missouri campuses. It is a public university serving more than 14,000 undergraduate, graduate and professional students. UMKC engages with the community and economy based on a three-part mission: visual and performing arts, health and life sciences, and urban affairs.

Whitehead Institute for Biomedical Research is a nonprofit, independent research and educational institution. Wholly independent in its governance, finances and research programs, Whitehead shares a close affiliation with the Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments.

This information is available to people with speech or hearing impairments by calling Relay Missouri at (800) 735-2966 (TT) or (800) 735-2466 (voice).

Media relations office at the Whitehead Institute contributed to this press release.


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