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Packard Center ALS News

The ALS Community Date: December 10, 2008
Subject: Robert Packard Center ALS News Network PACKARD STUDY SHOWS BOOSTING NATURE EXCEPTIONALLY HELPFUL IN ALS ANIMALShttp://www.alscenter.org/news/press/081210.cfm "What we're doing is highjacking the cell's normal pathway andupregulating it to make the motor neurons stronger, more able towithstand assault." In a study that demonstrates a much-anticipated proof of principle,scientists report today that that raising activity of a natural detoxsystem in the body can counteract the progressive loss of nerve cellsthat marks neurodegenerative disease, significantly delaying the onsetof disease and extending life. The research, led by Packard Center scientist Jeffrey Johnson at theUniversity of Wisconsin, was carried out on two different mouse modelscarrying the human gene for a familial type of ALS (Lou Gehrig'sdisease) and on cultures of motor neurons at risk of death from thegene. Studies elsewhere have shown that action of the detox system benefitsmodels of acute injury, such as stroke. This new work, however, revealsthat ramping up this system in live animals is effective against achronic neuron-killing disease such as ALS and that the benefits canoccur before its onset. Johnson's ongoing encouraging studies of the principle in Parkinson's,Huntington's and Alzheimer's disease models suggest its broadapplication. The published research also verifies key parts of the protectivepathway, suggesting new targets for therapies to come. "Even though wedid this study in a mutant mouse model," Johnson says, "this pathway -and the reason it's needed - is the same in humans. That's true,studies show, both in patients with the familial form of ALS or with themore common sporadic form. "We believe that bodes well that our resultswill apply to ALS in general," Johnson says. An account of the research appears this week in the Journal ofNeuroscience. Amyotrophic lateral sclerosis is the most common adult-onset disease ofmotor neurons - those that spark movement. It destroys motor neurons inthe spinal cord, brain stem and in higher brain centers specific formovement. The current study centers in part on a detox system that's gottenincreasing attention in the last decade. Cells rely on the so-calledphase II detoxification enzymes - the same system that broccolichemicals stimulate - to blunt the flood of damaging free radicals thatoccurs in many illnesses, including ALS. In the nervous system, it's asort of Neuroprotection R Us. Johnson has focused on what activates that system, what turns on thebattery of genes coding for its protective proteins. A body of work, including his, shows that the main "on" switch for theresponse is a complex dubbed Nrf2-ARE. And what caught Johnson's eyewere places in which Nrf2-ARE is most active. These are the astrocytes -star-shaped cells found widely in the central nervous system. It's no surprise that they'd carry a detox package, Johnson says; thenervous system's complexity and high energy requirement make itespecially vulnerable to damage. Astrocytes are companion cells to motor neurons, exchanging manymolecules with them and, in general, shaping their survival. Becausepart of this conversation involves the Nrf2-ARE pathway, astrocytesbecame a focal point of the study. "We reasoned that upping Nrf2-ARE inneighboring astrocytes might protect neurons in chronic distress,"Johnson explains. The team explored this possibility in rodents. They created transgenicmice whose astrocytes overproduced Nrf2. As a test of the protectivepower of the Nrf2-ARE pathway, they then crossed those mice with ALSmodels. (ALS model mice carry the human SOD1 gene that causes thatdisease in some families.) Normally, such mice die in 128 days. But those with Nrf2over-expressing astrocytes lived some 21 days longer - that's highlysignificant in this field. Also, onset of disease was delayed by 17days. In follow up tissue studies, the team showed that normalnerve-muscle connections held much longer - they deteriorate in ALS mice- keeping muscles active longer and slowing atrophy. The same studieswith a second type of ALS model mouse showed similar benefits. Also revealing was the team's research that focused on cell cultures.It built on earlier work by the study's first author Marcelo Vargas.When Vargas layered healthy young motor neurons atop a layer ofastrocytes from ALS mice, 40 percent of the motor neurons died. In thisnew work, the team placed the healthy motor neurons atop a layer ofastrocytes from the ALS-Nrf2 combo mice. That completely reversed thetoxic effect. "What's so interesting," Johnson says, "is that the mutant gene isstill in the astrocytes; but adding Nrf2 to them neutralizes itseffects. That saves the neurons." Finally, to help explain what actually was protecting the motorneurons, the team checked neighboring astrocytes for the moleculeglutathione. Glutathione is the major antioxidant source in cells,Johnson says. It's a key part of nerve cells' Phase II protectivepathway, which branches out in a host of specific directions afterglutathione is formed. The effect is akin to passing out rifles to amotley group of vigilantes. Astrocytes cultured from the Nrf2-bountiful mice had twice the usualconcentration of glutathione. Further tests showed that protection ofthe nearby motor neurons depended on glutathione secretion into theirenvironment. "It's extremely difficult to increase glutathioneexperimentally in the central nervous system," Johnson explains. "Youcan't just shoot it into people or animals. But we found a 25 percentincrease in the molecule in the spinal cords of the Nrf2-ALS mice. "What we're doing," he adds, "is highjacking the cell's normal pathwayand upregulating it to make the motor neurons stronger, more able towithstand assault. "It shows that by targeting astrocytes, it's possible to improve theirbenefits to motor neurons and thus alter the course of ALS. Our workalso validates Nrf2 as a viable target for therapy in chronicneurodegenerative disease." Delinda Johnson, Daniel Sirkis and Albee Messing were also members ofthe University of Wisconsin research team. The study was funded by theRobert Packard Center for ALS Research at Johns Hopkins, the ALSAssociation and NIH grants. ___________________________________ About The Robert Packard Center for ALS Research at Johns Hopkinswww.alscenter.org Located in Baltimore, the Robert Packard Center for ALS Research atJohns Hopkins is a worldwide collaboration of scientists aimed atdeveloping 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 thedisease. Its research is meant to translate rapidly from the lab benchto the clinic, largely by eliminating time spent waiting for grants andlowering institutional barriers to sharing scientific results. Scientists and clinician members of the Packard Center have moved drugsreliably and rapidly from preclinical experiments to human trials.Direct or indirect links to international biotech or pharmaceuticalcompanies bring the infrastructure and experience needed to makepromising drugs into therapies. Packard scientists are the first to propose and test a combinationapproach to drug therapy, a tactic that has worked for AIDS, cancer andother diseases. ALS is a progressive, disabling neuromuscular disease that causescomplete paralysis and loss of function - including the ability to eat,speak and breathe. ALS progresses quickly and is not curable. Mostpatients die within five years of diagnosis. _________________________________________Rebecca BergerResearch Program CoordinatorRobert 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 BergerResearch Program CoordinatorRobert 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