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CELL BIOLOGY Cell Death Pathway Found with Link to Alzheimer'sAn HMS researcher has uncovered a novel mechanism by which cells kill themselves, a discovery that provides a new direction for cell death research and suggests a potential treatment for Alzheimer's disease. Junying Yuan, associate professor of cell biology, describes her results in the Jan. 6 Nature.
The study continues Yuan's research on the complex mechanisms of cellular suicide, or apoptosis, a topic of intense interest because of its role in diseases like Alzheimer's, cancer, multiple sclerosis, and ischemia. Every cell is equipped with an intrinsic suicide mechanism, important for the homeostasis of tissues, development of the body, and removal of infected or damaged cells. However, when something goes wrong, cell death may spread, as in Alzheimer's, or may be abnormally suppressed, as in certain cancers. Much of apoptosis research has focused on caspases, a group of proteases that regulate the cell death mechanism in mammals. The decision to undergo apoptosis is a complex chain of events in which each caspase has a specific function, from responding to death stimuli at the cell membrane to executing the dissolution of the cell. By targeting specific caspases, researchers hope to find ways of controlling apoptotic signals in the cells to treat disease. Yuan's latest research, on caspase-12, reveals a pathway of cell death through the endoplasmic reticulum (ER), the site of protein production in the cell, and shows a direct relationship between caspase-12 and a protein involved in the development of Alzheimer's. The data, according to Yuan, suggest that "if we can make a specific inhibitor to caspase-12 then we may be able to delay the onset of Alzheimer's disease." Characterizing a CaspaseThis particular caspase has been a stumbling block for Yuan's team. After studying it for about two years, the researchers still had not found the right conditions for activating it to determine its role in apoptosis. Then Toshiyuki Nakagawa, a postdoc in Yuan's lab, decided to try a fractionation study to identify where the caspase was located in the cell. "It was sort of a desperate action," Yuan concedes. What they found was surprising: caspase-12 was very clearly located in the ER, rather than floating in the cytosol like most other caspases.Cells respond to a variety of apoptotic signals: DNA damage in the nucleus, free radical injury to the mitochondria, stimulation of death receptors on cell membranes, and the buildup of proteins in the ER. It is this latter stimulus, ER stress, that emerged as the key to activating caspase-12. The team found that caspase-12, located specifically in the ER, responded directly to ER stress but not to other apoptotic stimuli. Conversely, cells in which caspase-12 was not expressed were resistant to ER stress. The discovery of such a clear relationship was surprising since researchers usually find that mechanisms of apoptosis involve several caspases in a cascade that is not completely understood. In addition, most previous research had focused on death signals in the mitochondria and at the cell membrane. "Nobody thought that there would be a caspase in the ER," Yuan says.
The Alzheimer's ConnectionResearchers have struggled to explain the process of neuronal degeneration in Alzheimer's patients, whose brains form plaques of the insoluble protein amyloid-beta. A-beta forms when proteases cleave the amyloid precursor protein (APP), a normal protein of the cell. A-beta has been shown to induce neuronal cell death, working in a deadly cycle of neurodegeneration: A-beta induces apoptosis, during which a caspase is activated that also cleaves APP, producing more A-beta. Though the exact relationship between this mechanism and the onset of Alzheimer's has not been determined, an A-beta inhibitor would be a promising potential treatment.Having discovered a caspase with ER specificity, Yuan's team then looked for a possible relationship between A-beta and caspase-12. One of the factors of ER stress is a loss of calcium homeostasis, an imbalance that can result from the presence of A-beta. The ER was also a possible target of A-beta in causing cell death because it is the location of APP in the cell. To look for a correlation, Yuan and her colleagues exposed caspase-12–deficient cells to A-beta, and found they were resistant to A-beta neurotoxicity. When treated with antisense caspase-12, fewer cortical neurons underwent apoptosis upon exposure to A-beta. These results suggest that caspase-12 is a necessary factor for apoptosis induced by A-beta as well as other ER stress–inducing signals. The discovery of a direct link between A-beta and caspase-12 has intriguing implications for Alzheimer's research and treatment. A caspase-12 inhibitor could potentially prevent A-beta–induced apoptosis, a significant factor in Alzheimer's-related neurodegeneration. Yuan notes that knockout mice that lack the gene for caspase-12 do not exhibit any apparent abnormalities. Since caspase-12 seems to be involved only in ER stress–related apoptosis and not in other apoptotic pathways, its suppression may not disrupt other normal functions of the cell. —Courtney Humphries |
Junying Yuan's research shows that inhibiting the protease caspase-12 may help prevent the neuronal degeneration of Alzheimer's disease.
Junying Yuan's team used a variety of techniques to pinpoint caspase-12 localization in the endoplasmic reticulum (ER). Above, immunostaining of caspase-12 in HeLa cells using an anti-caspase-12 monoclonal antibody shows a ringlike stain around the nucleus that corresponds to the location of the ER in the cell.