Discovery sheds new light on Alzheimer’s and related diseases
(NOVATO, CA) - Billions of cells in the human body commit suicide each day, and the control of this suicide process plays a key role in such diverse processes as cancer, Alzheimer’s disease, and fetal development. The suicide process is called apoptosis, and a major scientific effort has gone into understanding its mechanism and developing modulators for use in several different diseases. Now scientists have shown that, despite previous claims to the contrary, apoptosis is not in fact the only program for cell death. Whereas apoptosis may be akin to a Windows-based program, there is also an alternative— something like a Macintosh-based program for cell death which scientists have dubbed "paraptosis". And perhaps most importantly, this new program is not affected by inhibitors of apoptosis, so scientists have their work cut out for them to develop modulators of the alternative pathway.
In the December 19 issue of the journal, Proceedings of the National Academy of Sciences, researchers from the Buck Institute for Age Research, the Burnham Institute, and the University of California at San Diego describe this alternative form of programmed cell death, which they dub "paraptosis". While apoptotic cell death is marked by fragmentation of the cell, its nucleus, and even its DNA, paraptosis shows none of the hallmarks of apoptosis; instead, paraptosis is characterized by the formation of empty spaces called vacuoles in the cell cytoplasm, along with mitochondrial swelling. Paraptotic cells are also resistant to agents that block apoptosis. Intriguingly, the characteristics of paraptosis have been observed in lower organisms that existed prior to the evolution of apoptosis, implying that paraptosis may actually turn out to be the older cell death program. Characterization of this alternative form of programmed cell death may lead to new insights into cell-death programs and their roles in development and degeneration, as well as novel therapeutic agents for cancer and neurodegenerative diseases.
"We are fascinated by paraptosis because it appears to occur during the development of the nervous system, as well as in some cases of neurodegeneration," said Dr. Dale Bredesen, President of the Buck Institute for Age Research and senior author on the study. "Therefore, although it may be the road less traveled in dying cancer cells, it appears to be a well worn path in brain cells, and therefore a potentially important therapeutic target." Dr. Sabina Sperandio, lead author, said that the next steps for this research will involve a "functional genomic characterization of the pathway, involving follow-up of pilot microarray studies and protein interaction studies."
Funding for this research was provided by the National Institutes of Health, the U.S. Army, the ALS Association, NATO, the American-Italian Cancer Foundation and the Department of Defense. For further information, contact Elizabeth Eshoo at the Buck Institute for Age Research in Novato, CA; tel: 415- 209-2261; cell: 415-254-1046; email: eeshoo@buckinstitute.org.
Dr. Bredesen is the founding President and CEO of the Buck Institute for Age Research. He is the author of more than 100 articles and book contributions in the field of neuroscience. Dr. Bredesen’s laboratory at the Buck Institute is working to define the basic chemistry and critical mechanisms of neural cell death, especially as they pertain to such age-associated diseases as ALS, Alzheimer's disease, and Parkinson's disease. A major goal of this research is the development of early diagnostic markers and therapies that will delay the onset and retard the progression of these diseases.
Dedicated entirely to biomedical research on aging and age-associated diseases, the Buck Institute is the only freestanding institute of its kind in the United States, and only one of three in the world. Located 20 miles north of San Francisco, its mission is to extend the healthy, productive years of life through basic research. Since its opening in July of 1999, the Buck Institute has brought together a multi-disciplinary group of researchers, utilizing state-of-the-art technologies and resources, to focus on the complex challenge of discovering the mechanisms of age-associated diseases and developing therapeutics to prevent these debilitating conditions. The Buck Institute is a non-profit, independent organization and seeks funding from government, foundation, corporate, and other sources to accomplish its mission. For further information visit the web site at www.buckinstitute.org.
An electron microscopic image of "paraptosis" is available at http://www.buckinstitute.org/press/paraptosis.htm
Journal
Proceedings of the National Academy of Sciences