HD Lighthouse Contributing Editor's Comment: The ubiquitin-proteasome system in a cell is supposed to recognize misfolded proteins, slice them up, and clear them away. It doesn't work well with the Huntington's Disease protein in brain cells. Rapamycin, being considered as a potential therapy, initiates autophagy which is another way that the HD protein can be cleared out. Autophagy is not a well understood process; Dr. Klionsky's work is answering questions which will help in the rational design of therapy for Huntington's Disease.
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Posted to the HDL: 08 Nov 2004

University of Michigan researcher examines the cell's housekeeping habits

The cells of higher organisms have an internal mechanism for chewing up and recycling parts of themselves, particularly in times of stress, like starvation and disease. But nobody is quite sure yet whether this recently discovered process protects cells, or causes damage. This process of internal house-cleaning in the cell is called autophagy - literally self-eating - and it is now considered the second form of programmed cell death (PCD). Apoptosis, the first kind of programmed cell death to be characterized, is now also known as Type I PCD. Genes governing Type II PCD, autophagy, have been identified recently in many species, starting with baker's yeast, and some of the environmental triggers that start the process are being found. But there is still quite a bit of science to do before autophagy can be understood as either a good thing or a bad thing. The evidence points both ways. "It's likely to be both, depending on when it happens," said Daniel Klionsky, a research professor at the University of Michigan Life Sciences Instituteand professor of molecular cellular and developmental biology and biological chemistry. Klionsky, who has been studying autophagy in yeast, has written a review article on the latest work in the field with post-doctoral fellow Takahiro Shintani that is featured on the cover of the Nov. 5 edition of Science magazine. Klionsky also recently edited the authoritative book on autophagy. A cell undergoing autophagy assembles tiny capsules called vesicles that surround and chew up parts of the cellular machinery from within. Autophagic vesicles have been seen in cells undergoing programmed cell death, but the evidence is not clear yet whether they're trying to protect the cell from apoptosis, or hastening its demise. "Autophagy is the only way to get rid of damaged parts of the cell without trashing the whole thing. So in a nerve cell, for example, you'd want autophagy to correct problems without destroying the cell." High levels of autophagic vesicles also have been noted in some forms of degenerative muscle disease, and in degenerative nervous system diseases like Huntington's, Parkinson's, Alzheimer's and ALS, (Lou Gehrig's disease). But it's not clear why the vesicles are accumulating. They may be building up because they aren't being used, or it may be that the distressed cells are producing more vesicles. "Until the genes for autophagy were found in yeast, the whole field was sort of stumped," Klionsky said. Now researchers are able to identify autophagy genes in humans and other organisms, including mice, and can tinker with the regulation of the process to see how it works. Cancer researchers have been trying to figure out how to turn apoptosis on as a way to have cancer cells kill themselves. Being able to control autophagy may prove useful as well, Klionsky said. In fact, any kind of disease where damaged parts accumulate inside the cell might benefit from being able to control autophagy, he said. "If you could turn it on at will, it could be used as a therapy," he said. Autophagy probably works both to promote and prevent cancer. Its works as a tumor suppressor when it limits cell size and removes damaged machinery in the cell that could generate free radicals or create genetic mutations. But, paradoxically, autophagy may protect cancer cells against some cancer treatments and it might also make cancer cells live longer by recycling cellular parts in the nutrient-poor environment inside a tumor. Intriguingly, a line of laboratory mice with suppressed autophagy also appears to have a higher rate of spontaneous tumors, Klionsky said.

Autophagy helps the cell fight infection by some kinds of invading bacteria and viruses, by cleaning them out of the cell's interior without having to discard the entire cell. As a result, some pathogens try to escape autophagy. For example, the virus that causes Herpes carries a gene that blocks autophagy. The bacteria that cause Legionnaire's Disease actually hide inside the vesicles to reproduce.

Autophagy may even provide a clue to the mythical fountain of youth. Autophagy activity is known to decrease with aging, and experiments in which autophagy was blocked in the C. elegans nematode worm resulted in dramatically shorter life spans for the 1 millimeter creatures. Conversely, more autophagy may prolong life. This fits with findings that caloric restriction can extend the life span in rats, since near-starvation triggers more autophagy as the cells recycle parts of themselves for fuel. Sustained autophagy may also increase longevity by protecting cells against free radical damage and mutations in DNA.

"This is becoming a very hot field," Klionsky said. "We have a lot of really interesting questions to explore in autophagy."

Tracked on the Lighthouse:
proteasome
autophagy

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Source: press release

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