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Two Birds with One Molecular Stone
UNLV biochemist Ron Gary is deeply interested in physiological processes affecting human health, a fact that’s not immediately obvious as one gazes down at the petri dishes positioned around his lab. But Gary’s molecular-level work with the cells housed in these dishes continues to yield important cancer-related discoveries and, more recently, potentially game-changing neuroscientific findings related to Alzheimer’s disease.
The Alzheimer’s discoveries were an outgrowth of the cancer research. Gary and his laboratory team were working to learn whether inhibiting the aberrant activity of a particular “signaling” enzyme, glycogen synthase kinase-3 (GSK-3), might slow the explosive growth of cancer cells. Because the enzyme has also been implicated in the development of Alzheimer’s, Gary’s team soon found themselves thinking about the ways in which inhibiting GSK-3 might affect a key component of that disease as well.
There are two microscopic structures that are characteristically found in the brains of Alzheimer’s patients: plaques and neurofibrillary “tangles.” At the molecular level, neurofibrillary tangles are perhaps the illness’s most distinguishing feature. The tangles are composed of tau — proteins that, when working normally, play a key role in transporting nutrients and other important materials throughout the cell. When tau proteins aggregate in the brain and form tangled clumps, the transportation system breaks down, cells begin to die, and Alzheimer’s symptoms appear.
Gary, a professor in UNLV’s department of chemistry and biochemistry, suspects that GSK-3 may be inadvertently inducing tau tangling by accelerating a process called phosphorylation — a crucial metabolic step by which, under normal circumstances, cells regulate various molecular processes.
“Though we don’t know why it becomes overactive and produces tangled tau, our thinking is that, if you could suppress or slow that phosphorylation activity of GSK-3, you could stop or slow the formation of tau tangles,” Gary says. “Then maybe you could prevent or slow the progression of Alzheimer’s.”
In order to reduce GSK-3 and suppress the formation of tangles, Gary says, researchers would need to develop an inhibitor, a compound or drug that would depress its activity. Gary and his team of students are working to do just that.
“We take human cells of brain origin, treat them with different drugs in a dish, and look at the molecular consequences of that treatment,” he said. “You can’t just eliminate the GSK-3 enzyme, because that would be problematic as well.”
Gary says a handful of key questions are guiding his lab team’s efforts. What are the consequences more broadly throughout the cell, and specifically, do different types of inhibitors do the same thing throughout the different areas where GSK-3 has a function? Or could different inhibitors have subtly different effects on GSK-3-related systems?
Gary says he’s also interested in examining beta-catenin, another important molecule influenced by GSK-3. Beta-catenin plays a crucial role in the control of cell growth. If out of balance, it could potentially be a contributing cause of cancer.
According to Gary, when you inhibit GSK-3 with the goal of reducing tau tangles, it seems likely you would also reduce the phosphorylation of beta-catenin.
“You would initially assume that any inhibitor that suppresses GSK-3 enzyme activity would have a similar effect on beta-catenin, but we found that different inhibitors have different effects on beta-catenin,” he says. “This is important because Alzheimer’s work covers everything from treating patients to the other end of the spectrum, looking at molecular effects in isolated cells. But if we ever want to use this class of compound to treat patients, we would want to know what else happens in the cell when you suppress tau phosphorylation by inhibiting GSK-3.”
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