Exactly how ALS - Lou Gehrig's disease - damages motor neurons is one of medical science's lingering mysteries. At least six mishaps within cells appear to contribute to the death of the nerves that enable muscle movement, but nothing stands out as the key problem.
Now new studies by a Canadian research team and Japanese collaborators, with support from the Packard Center for ALS Research at Johns Hopkins, strengthen earlier theories that whatever ultimately tips motor neurons onto their downhill path likely comes from outside the cells. The work describes a mechanism in which a warped, toxic molecule is secreted from cells into a motor neuron's environment, where it harms the neuron.
The studies, described in this month's issue of Nature Neuroscience, could focus therapy research on easier-to-access areas outside of cells.
Led by Packard scientist Jean-Pierre Julien of Quebec's Laval University, the work is largely based on mouse models of ALS - animals engineered with a mutant human gene responsible for a familial form the disease. Mice carrying the mutant SOD1 gene develop ALS and die. Those with normal SOD1 are fine.
In some earlier, rather exotic studies where only some mouse cells were made to carry mutant SOD1 genes, Julien's team showed, to their great surprise, that even though motor neurons may carry mutant genes, they apparently don't die as long as neighboring cells are normal. And, conversely, having neighbors with mutant SOD1 can trip motor neuron death even if the motor neurons themselves have the undamaged version. Other Packard scientists have confirmed the unusual results that say a motor neuron's surroundings are all-important in developing disease-what they call the "bad neighborhood" theory.
In the new studies, Julien's team found that misshapen, mutant SOD1 is preferentially "booted out" of nervous system cells - secreted by motor neurons and other neighboring cells - into cell surroundings. Once there, the researchers show, the mutant SOD1 is directly toxic to motor neurons it encounters. Mutant SOD1 can also rouse nearby immune cells, the microglia, to release neuron-harming agents.