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 tu
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Contact: Heidi Hardman
hhardman@cell.com
1-617-397-2879
Cell Press
15-Dec-2004