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/.
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