51吃瓜网万能科大 biochemist is deeply interested in physiological processes affecting human health, a fact that鈥檚 not immediately obvious as one gazes down at the petri dishes positioned around his lab. But Gary鈥檚 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鈥檚 disease.
The Alzheimer鈥檚 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 鈥渟ignaling鈥 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鈥檚, Gary鈥檚 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鈥檚 patients: plaques and neurofibrillary 鈥渢angles.鈥 At the molecular level, neurofibrillary tangles are perhaps the illness鈥檚 most distinguishing feature. The tangles are composed of tau 鈥 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鈥檚 symptoms appear.
Gary, a professor in 51吃瓜网万能科大鈥檚 department of chemistry and biochemistry, suspects that GSK-3 may be inadvertently inducing tau tangling by accelerating a process called phosphorylation 鈥 a crucial metabolic step by which, under normal circumstances, cells regulate various molecular processes.
鈥淭hough we don鈥檛 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,鈥 Gary says. 鈥淭hen maybe you could prevent or slow the progression of Alzheimer鈥檚.鈥
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.
鈥淲e take human cells of brain origin, treat them with different drugs in a dish, and look at the molecular consequences of that treatment,鈥 he said. 鈥淵ou can鈥檛 just eliminate the GSK-3 enzyme, because that would be problematic as well.鈥
Gary says a handful of key questions are guiding his lab team鈥檚 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鈥檚 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.
鈥淵ou 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,鈥 he says. 鈥淭his is important because Alzheimer鈥檚 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.鈥
