[BillO]

The ALS Community
Date: September 4, 2008
Subject: Robert Packard Center ALS News Network View this article online at:http://www.alscenter.org/news/briefs/080903.cfm

NEW STUDY ADDS AN INTRIGUING BIT TO ALS/MITOCHONDRIA PUZZLE In ALS, trouble is afoot in mitochondria. And while nobody knows why, precisely, new research is showing how seemingly slight disruptions in their normal interactions with the rest of the cell could have great consequences. "Is this the key to understanding the process of ALS?" asks Packard grantee Giovanni Manfredi. "We don't know." But given the importance of mitochondria – the organelles that are the body's major energy source– his research follows a promising avenue for learning about the disease and finding targets for its therapy. It also shines light on how mitochondria interact with other cell systems – a complex and little studied give-and-take that may be involved in a number of diseases. A report on the work appeared in this month's online Journal of Biological Chemistry. Manfredi is a neuroscientist with the Weill Medical College of Cornell University. For several years, Manfredi and others have known that ALS's symptoms begin in both model mice and humans at the same time that mitochondria become misshapen and start to fall apart. Both the animal models and people with the most common familial type of ALS carry a mutated form of the SOD1 (super oxide dismutase) gene that causes their disease. Logically, then, Manfredi's team has been trying to piece together theSOD1_sick mitochondria connection. It's part of a major effort by ALS researchers to see, overall, how SOD1 can cause the disease. Normal SOD1, a molecule manufactured in the cell's cytoplasm, is able to slip through both of the outer and inner membranes that characterize mitochondria. Once inside, it performs a useful service, clearing away toxic charged molecules – free radicals – that build up. Other proteins are "imported" into mitochondria as well, coming in to do various tasks. Not every molecule can enter, however – only those shaped so they’re compatible with mitochondrial systems that pull them in like so many flounder on a fisherman's deck. In this recent research, Manfredi has focused on an enzyme protein called KARS, one normally given easy entry. Inside mitochondria, KARS plays a quiet but necessary part in the manufacture of specific molecules tailored to their use. What Manfredi discovered was that mutant SOD1, but not healthy (wild type) SOD1 interacts physically with KARS, causing an abnormal structural change that prevents or disrupts KARS' being imported into mitochondria. "This all happens on the mitochondrial surface," Manfred explains. "KARS, in essence is abducted by mutant SOD1, resulting in its misfolding." Not only does this prevent KARS from doing its useful role but also, Manfredi speculates, clumps of misfolded KARS and mutant SOD1 may so gum the surface of mitochondria that other necessary proteins are kept from their normal transport in. Further, says Manfredi, warped KARS is likely to be recognized as "bad” by the cell's housekeeping machinery, placing a strain on that system swell. And neurons, he says, are likely to be more sensitive to these changes than other cells. In the mouse models, for example, non_nervoussystem tissues looked undamaged. "So we see that a mitochondrial problem can cause ongoing difficulties elsewhere in the cell," says Manfredi. "Our work adds to the suggestion that there's a system of protein import in mitochondria whose malfunction could be involved in disease such as ALS*. The idea is an intriguing one." * Studies elsewhere show that abnormalities in another mitochondrial entering protein similar to KARS is responsible for the neurodegenerative Charcot_Marie_Tooth disease, a hereditary illness that affects sensation and movement in the lower legs, mostly. ___________________________________ About The Robert Packard Center for ALS Research at Johns Hopkinswww.alscenter.org Located in Baltimore, the Robert Packard Center for ALS Research at Johns Hopkins is a worldwide collaboration of scientists aimed at developing therapies and a cure for amyotrophic lateral sclerosis (ALS),also known as Lou Gehrig’s disease. The Center is the only institution of its kind dedicated solely to the disease. Its research is meant to translate rapidly from the lab bench to the clinic, largely by eliminating time spent waiting for grants and lowering institutional barriers to sharing scientific results. Scientists and clinician members of the Packard Center have moved drugs reliably and rapidly from preclinical experiments to human trials. Direct or indirect links to international biotech or pharmaceutical companies bring the infrastructure and experience needed to make promising drugs into therapies. Packard scientists are the first to propose and test a combination approach to drug therapy, a tactic that has worked for AIDS, cancer and other diseases. ALS is a progressive, disabling neuromuscular disease that causes complete paralysis and loss of function _ including the ability to eat, speak and breathe. ALS progresses quickly and is not curable. Most patients die within five years of diagnosis. _________________________________________Rebecca Berger Research Program Coordinator Robert Packard Center for ALS Research at Johns Hopkins5801 Smith Avenue | McAuley Suite 110Baltimore, MD 21209410.735.7678 direct410.735.7680 faxrberger6@jhmi.edu www.alscenter.org _________________________________________Rebecca Berger Research Program Coordinator Robert Packard Center for ALS Research at Johns Hopkins5801 Smith Avenue | McAuley Suite 110Baltimore, MD 21209410.735.7678 direct410.735.7680 faxrberger6@jhmi.eduwww.alscenter.orgwww.fiesta5K. org ************************************************** ******************************Click on the link below to unsubscribemailto:sympa@lists.johnshopkins.edu?sub ject=unsubscribe%20alscenter&body=PLEASE%20SEND%20 THIS%20EMAIL%20OUT%20FOR%20UNSUBSCRIBING Please follow the instructions below if the above link does not work: Compose an email to: sympa@lists.johnshopkins.edu With Subject: unsubscribe als center Note: 'unsubscribe als center' should be on the SUBJECT line, NOT IN THE MESSAGE BODY. 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