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Study Suggests Dramatic Way to Step Up Protection of Endangered Cells in ALS, Other Diseases Pharmaceutical companies are very interested. Jeff Johnson must feel like the little kid who shot off his cap pistol just at the finale to a July 4th fireworks show. He pulled the trigger and things took off, far beyond what he’d ever expected. For Johnson, a Packard Center scientist at the University of Wisconsin, his laboratory’s version of “shock and awe” is focused on finding that a molecule they’ve studied acts as a key, of sorts, to open a cell’s built-in protective system against nerve cell insults. “The molecule brings up all of a cell’s
The work suggests that cell defenses could be heightened early on in times of severe nervous system disease to protect cells from harm. In the studies, both with cell cultures and with live lab mice, Johnson’s team found that increasing the availability of the key molecule, abbreviated Nrf2, could protect animals specifically exposed to toxins that mimic effects of Huntington’s disease (HD). The researchers injected one brain half in healthy mice with cells engineered to overproduce Nrf2. The cells — astrocytes — are a main site of Nrf2 production and soon settle into nearby brain tissue. The other brain half received astrocytes that weren’t Nrf2 enriched. A few weeks later, after the animals’ brains were challenged with a neurotoxin, the brain halves without the Nrf2-rich cells showed obvious holes left by dying cells, typical of HD. But the treated brain halves were “absolutely fine, as far as we could tell,” Johnson says. “It was an amazing response,” he says, “certainly beyond our expectations.” What ties this in with ALS and other neuro diseases like Parkinson’s and Alzheimer’s? In all of them, there’s a damaging process similar to what the toxins in his study unleashed — high production of toxic free radicals. The free radicals come, in part, from glitches in the cell’s mitochondria — small bodies that produce the bulk of a cell’s energy. What causes the glitches in all of these diseases is something neuroscientists as yet only guess at. It’s an area of fevered research. But for now, it’s important to know that Nrf2 — and the protective reactions it unleashes — lessen harm. “It’s something like putting mitochondria on steroids,” says Johnson. And it’s only when the disease process finally overwhelms Nrf2s capabilities that things start to go downhill. “We want to enhance this pathway, to offset damage early on,” he adds. Currently, Johnson is looking into Nrf2-enhancing capabilities offered by existing drugs, stem cells or gene therapy. Under a Packard Center grant, Johnson has been testing his Nrf2 approach on the mutant SOD1 mice that model ALS, in this case to try to quiet motor neuron damage. That work, which he says “is going very well,” will be submitted for publication shortly. Pharmaceutical companies are becoming very interested in the studies, he says, because of Nrf2’s potential to help a broad range of diseases and conditions. |
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