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Late-Blooming Molecule Could Be Key Target
|Dr. Akira Sawa|
I work with what most people think of as one of the most boring molecules in science,” says Akira Sawa, M.D., Ph.D., of an enzyme that now looks to be anything but that. Indeed, GAPDH—the molecule’s acronym—shows signs of being a key player in cell death. “It could play a role in the wasting away of brain tissue in Alzheimer’s, Huntington’s or Parkinson’s disease, for example, or in any of the more dominantly psychiatric illnesses where there’s brain cell loss,” Sawa says.
Most people, if they’ve even heard of glyceraldehyde-3-phosphate dehydrogenase, would have run into it in high school biology, as part of the basic pathway cells use to extract energy. And there it’s stayed, in most researchers’ minds: a ho-hum housekeeping molecule you learn about for a test and forget.
But Sawa, who’d landed a highly competitive fellowship at Hopkins in mentor Sol Snyder’s neuroscience lab, came across a journal article about GAPDH—in itself an oddity, he thought—that stuck with him. The piece suggested that damping down the molecule might protect cells from death. Specifically, they might be turned away from apoptosis, a cascade of injury-prompted reactions—hard-wired into cells—that ends in death.
For the past decade, Sawa has followed GAPDH’s path, hoping not only to clarify apoptosis but also to identify a reasonable place to stop it, as a therapy for brain disease. By developing ways to pinpoint GAPDH, Sawa and colleagues discovered that, in cells held in the grasp of apoptosis, the molecule slips into the nucleus. There it somehow prompts the end stages. Blocking its entry, they found, keeps neurons and a variety of lab-cultured cells alive.
More recent studies reveal that the GAPDH shows a different face in cells under the stress of disease. Then, the enzyme gets chemically adjusted, enabling it to team with a smaller molecule built to cross into the nucleus. All this leads Sawa to conclude that GAPDH is a key sensor, one that can respond to the warped chemistry of a cell in trouble and help send it to the graveyard.
Discovering that has taken persistent basic science. “But I haven’t lost the clinician’s heart,” says Sawa, who was trained as a psychiatrist in Japan. “I’m still very much interested in therapy.” Enter deprenyl. Sawa’s team knew the drug from large clinical trials for Parkinson’s disease. Deprenyl was thought able to replace an agent in short supply in PD patients. Though the trial results weren’t exciting, the drug’s secondary effect—keeping GAPDH outside the nucleus—has interested the Hopkins team.
Today they’re testing deprenyl on animal models of Parkinson’s disease, to see if it slows or prevents death. In addition, Sawa hopes to find if his ability to track GAPDH’s undesirable, traveling version might help detect Alzheimer’s disease well before symptoms start, when something, potentially, might be done.
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