New Route To Parkinson's Found In Cells' 'Garbage Disposal' System

[John Cottingham <jcott@xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx>]

The source of this article is Nature: http://tinyurl.com/3uovp

New Route To Parkinson's Found In Cells' 'Garbage Disposal' System
Researchers have known that mutations in a key gene called parkin are a major 
cause of Parkinson's disease (PD). Now they have discovered a new mechanism by 
which the parkin gene can be compromised, a finding that they say could lead to 
new drugs for the disorder.

Andrea Lozano, Senior Scientist at the Toronto Western Research Institute, of 
University Health Network and Professor of Surgery at the University of Toronto 
and colleagues found that the protein produced by a gene called BAG5 inhibits 
parkin activity and the action of another protein, called Hsp70, a "chaperone" 
that works with parkin. They found in studies with rats that BAG5 enhances the 
death of the dopaminergic neurons targeted by Parkinson's and that inhibiting 
the gene reduces such death.

Parkin is part of the cell's "garbage disposal" system that rids the cell of 
unwanted proteins by degrading them. Mutations of parkin eliminate its ability 
to chemically "tag" such proteins to designate them for destruction in the 
cell's proteasome--a process called ubiquitinylation. Loss of such ability 
causes such protein garbage to aggregate into lethal clumps in neurons--a 
hallmark of many neurodegenerative diseases. In the brain, the parkin protein 
works with Hsp70, which helps correct the folding of misfolded proteins.

BAG5 is one of a family of BAG proteins known to interact with other proteins 
to aid a variety of cell processes. The structure of BAG5 led Lozano and 
colleagues to explore whether it might play a role in the proteasome, along 
with parkin and Hsp70.

Their experiments revealed that BAG5 was activated when dopaminergic neurons 
were injured, suggesting a role in neurodegeneration. Experiments also revealed 
that BAG5 inhibits Hsp70 and interacts directly with parkin, inhibiting its 
activity. This inhibition, they found, enhances the formation of protein 
aggregates, and this formation was inhibited when the researchers shut down the 
activity of BAG5. In other test tube studies, the researchers also found that 
BAG5 inhibited parkin's ability to protect cells against proteasome dysfunction 
and cell death.

In experiments with rats, the researchers found that BAG5 enhanced the 
degeneration of dopaminergic neurons and that inhibiting BAG5 increased 
neuronal survival.

"Based on our findings, we propose a novel mechanism for neurodegeneration in 
which BAG5 interacts with both parkin and Hsp70, resulting in decreased parkin 
and Hsp70 function, two outcomes that are deleterious to cell survival," 
concluded the researchers. "Given the role of BAG5 in modulating 
ubiquitinylation, protein aggregation, and cell death, it may serve as a useful 
therapeutic target for neurodegenerative diseases such as PD."

###

The other members of the research team include Suneil K. Kalia, Sang Lee, and 
Li Liu, of the Toronto Western Research Institute of the University of Toronto; 
Patrice D. Smith, Stephen J. Crocker, and David S. Park, of the Neuroscience 
Research Institute of the University of Ottawa; Thorhildur E. Thorarinsdottir 
and Edward A. Fon, of the Centre for Neuronal Survival of McGill University; 
and John R. Glover, of the Department of Biochemistry of the University of 
Toronto. This work was supported by the Canadian Institutes of Health Research 
(CIHR) (S.K.K., J.R.G., E.A.F., D.S.P., A.M.L.); Michael J. Fox Foundation 
(T.E.T.); and Parkinson's Society of Canada (D.S.P.).

Suneil K. Kalia, Sang Lee, Patrice D. Smith, Li Liu, Stephen J. Crocker, 
Thorhildur E. Thorarinsdottir, John R. Glover, Edward A. Fon, David S. Park, 
and Andres M. Lozano: "BAG5 Inhibits Parkin and Enhances Dopaminergic Neuron 
Degeneration"

The context and implications of this work are discussed in a Preview by Kenny 
K.K. Chung and Ted M. Dawson of the Johns Hopkins University School of Medicine.

Publishing in Neuron, Volume 44, Number 6, December 16, 2004, pages 931?945. 
http://www.neuron.org/.


--------------------------------------------------------------------------------

This story has been adapted from a news release issued by Cell Press.

----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:listserv@xxxxxxxxxxxxxxxxxxxx
In the body of the message put: signoff parkinsn