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Muscles More Than Passive Victims in ALS, Study Suggests Work offers a new line of therapy research to slow ALS.
There’s some science behind that opinion. A recent study by Packard researcher Don Cleveland showed that if the muscles of model mice — and only the muscles — held active genes for inherited human ALS, the mice stayed healthy. That would seem to nix muscles as a source of ALS. New work by Packard scientist Jeffrey Johnson, however, suggests that we shouldn’t be quick to dismiss muscles. It also offers a new therapeutic path that he’s actively investigating — one that works by boosting natural efforts to stave off ALS’s worst effects. In his several years as a Packard grantee, Johnson’s work has dealt with one of the body’s built-in detox systems. Cells rely on the so-called phase II detoxification enzymes — the same system that broccoli chemicals stimulate — to blunt the flood of damaging free radicals that occurs in many illnesses, including ALS. More specifically, Johnson has focused on what activates that system, what turns on the battery of genes coding for its enzymes. A body of research, including Johnson’s, shows that the on switch for phase II involves a specific protein and chemical cascade, dubbed the Nrf2-ARE pathway. And the studies go one step more to show that when the ARE complex is in place and active, whether in cultures or in live animal models exposed to toxic situations, nerve cells get significant protection from damage. In addition, other pathways important to cells’ general working are strengthened. “So,” says Johnson, “this system bears investigating for ALS.” Recently, he followed activation of the Nrf2-ARE path in two different animal models of ALS. A method for visually tracking the process let his team see exactly where this took place and also let him mark the time when cells turned the Nrf2-ARE system on. “The main point,” he says, “is that pathway activation seems to be a very early indicator of stress, and it appears in the muscles very early in the disease process, even before symptoms begin.” “What we’re speculating, then, is that, in ALS, the Nrf2-ARE response in muscles is due to something subtle going wrong at the level of the synapse between the motor neuron and the muscle,” Johnson says. Of special interest therapy-wise, he adds, is that the response varies within muscles, depending on the type of muscle fiber. Skeletal muscles affected by ALS contain a mix of “slow twitch” or type I fibers that allow sustained aerobic activity and “fast” type II fibers that exhibit greater force but that fatigue more quickly. Johnson’s team found that the Nrf-2-ARE system is activated only in type I fibers. He thinks it’s no coincidence that the usual activity between motor nerves and the type I muscle lasts longer — resists paralysis longer — than in type II. And it’s extremely interesting that the pattern of activation follows a path from type I muscle fibers to nerve cells to key parts of the spinal cord that mimics human ALS. “Of course it’s speculative at this stage, but if we could activate the system in type II fibers, that might stave off the worst symptoms longer and affect ALS progression,” he explains. Johnson’s working to that end. He’s now testing an ALS mouse model in which those very fibers have been engineered to turn on the dormant protection within. The work was jointly funded by The Robert Packard Center for ALS Research at Johns Hopkins and the ALS Association. This study will appear in the journal, Experimental Neurology and can be accessed currently as an Article in Press through the following link: http://dx.doi.org/10.1016/j.expneurol.2007.05.026 |
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