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Hopkins Researchers Find Missing Link Between Major Proteins In Parkinson's Disease

Date:
October 16, 2001
Source:
Johns Hopkins Medical Institutions
Summary:
A new study identifies an important link between the two main inherited forms of Parkinson's disease (PD), and might also connect them to non-inherited versions, Hopkins scientists report in the October issue of Nature Medicine.

A new study identifies an important link between the two main inherited forms of Parkinson's disease (PD), and might also connect them to non-inherited versions, Hopkins scientists report in the October issue of Nature Medicine.

The inherited forms are marked by alterations, or mutations, in one of two different proteins, parkin or alpha-synuclein (aS), but how they might lead to the same disorder isn't well understood. One answer, the Hopkins scientists report, is that both proteins interact with a third protein, synphilin, and the mutations disturb this interaction.

While it is still not known how this disturbance might result in the death of certain nerve cells that characterizes PD, the common thread offers clues for further studies, says Ted Dawson, M.D., Ph.D, of the Johns Hopkins School of Medicine.

"We were trying to see if the genetic mutations converge with what's known about the non-inherited disease, as is the case for Alzheimer's disease," explains Dawson, professor of neurology and neuroscience and director of the Program in Neural Regeneration and Repair for the Johns Hopkins Institute for Cell Engineering. "And now, all roads in Parkinson's disease seem to lead to alpha-synuclein."

The study was funded by the United States Public Health Service and the Edward T. and Anna Mitchell Family Foundation.

In Parkinson's disease, nerve cells that produce a chemical called dopamine die, starving the brain of a crucial messenger. Many of these dead and dying nerve cells contain protein blobs that include parkin, aS and synphilin. Understanding the formation of these clumps, called Lewy bodies, might eventually help identify targets for new treatments, Dawson says.

To begin with, the study sheds some light on how these three proteins normally interact. Parkin was already known to mark certain proteins for destruction by recruiting a fourth protein called ubiquitin. Synphilin was only known to bind to aS, whose normal function isn't understood.

The experiments showed that parkin binds to synphilin, and via synphilin to aS. Under the right circumstances parkin tags these proteins with ubiquitin, says Dawson. They also showed that the common mutations in inherited PD prevent parkin from marking the other proteins for destruction.

Based on the new information, gleaned from experiments with pure proteins and with cells, Dawson suggests one stimulus behind Lewy body formation might be a malfunctioning and toxic aS. Lewy bodies, which also contain ubiquitin, could essentially be a protection mechanism gone awry, he says.

"We suspect that the destruction pathway and the action of ubiquitin might be very important in Parkinson's disease, that perhaps the altered destruction of alpha-synuclein could be the common thread in causing these neurons to die," says Dawson. "Exactly how isn't understood, but we're continuing to study it."

The researchers are testing whether they can manipulate the extent of Lewy body formation by crossing mice specially engineered to have different alterations in parkin, aS or synphilin.

Co-authors with Dawson are Kenny Chung, Yi Zhang, Kah Leong Kim, Yuji Tanaka, Hui Huang, Jun Gao, Christopher Ross and Valina Dawson, all of The Johns Hopkins University School of Medicine.

Related Web sites:

http://www.nature.com/nm

http://www.med.jhu.edu/neurosci/welcome.html


Story Source:

The above story is based on materials provided by Johns Hopkins Medical Institutions. Note: Materials may be edited for content and length.


Cite This Page:

Johns Hopkins Medical Institutions. "Hopkins Researchers Find Missing Link Between Major Proteins In Parkinson's Disease." ScienceDaily. ScienceDaily, 16 October 2001. <www.sciencedaily.com/releases/2001/10/011015055336.htm>.
Johns Hopkins Medical Institutions. (2001, October 16). Hopkins Researchers Find Missing Link Between Major Proteins In Parkinson's Disease. ScienceDaily. Retrieved July 25, 2014 from www.sciencedaily.com/releases/2001/10/011015055336.htm
Johns Hopkins Medical Institutions. "Hopkins Researchers Find Missing Link Between Major Proteins In Parkinson's Disease." ScienceDaily. www.sciencedaily.com/releases/2001/10/011015055336.htm (accessed July 25, 2014).

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