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Third Public Conference: Cellular Aging
and Apoptosis The Proteases to Die For Speaker In 1993, Dr. Yuan broke new ground in apoptosis research by identifying both a cell-death gene in C. elegans and its mammalian homologues. This gene product, called Ced-3, was the first member of the caspase family of proteases - a group of enzymes now recognized as ubiquitous in programmed cell death. More recently, her laboratory in the Department of Cell Biology at Harvard Medical School has uncovered a direct link between a caspase and Alzheimer's disease. Dr. Yuan has been an Associate Professor at HMS since 1996, having joined the faculty in 1992. Her investigations of cell death mechanisms in the nematode C. elegans began when she was a graduate student in the laboratory of Dr. H. Robert Horvitz at the Massachusetts Institute of Technology. She received her Ph.D. in Neuroscience from Harvard University in 1989. Topic While C. elegans has only one known caspase, humans have at least 14 of these cysteine proteases, now widely regarded as critical mediators of apoptosis signal transduction and execution. Caspases can be activated by apoptotic signals that target different cell compartments, such as death receptors located on cytoplasmic membrane, DNA damage to nuclei, free radical insult of mitochondria, and the build-up of proteins in the endoplasmic reticulum. Experiments in Dr. Yuan's laboratory showed that the latter stimulus, known as ER stress, specifically activates caspase-12, an odd duck in the caspase family because it concentrates in the ER instead of floating in the cytosol with its relatives. One well-known cause of ER stress in neurons is the accretion of amyloid-beta,
the insoluble protein that forms plaques in the brains of patients with
Alzheimer's disease. As A-beta causes brain cells to die, a byproduct
of their deaths is a caspase that cleaves amyloid precursor protein,
thereby producing more of the deadly A-beta. Looking at this situation,
and knowing that they had found an ER-specific caspase, Dr. Yuan and
her colleagues wondered if there might be a promising connection between
the two. When they exposed caspase-12 deficient cortical neurons to
A-beta, the cells were resistant to A-beta toxicity. Dosing the neurons
with antisense caspase-12 also reduced apoptosis. Experiments with caspase-12
knockout mice further supported a link between A-beta and this ER-specific
caspase. Clearly a caspase-12 inhibitor would be a promising antidote
to the neurodegeneration that occurs in Alzheimer's disease, Dr. Yuan
said.
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