Researchers Uncover New Toxic Mechanism In ALS
- From: alscenter@jhmi.edu
- To: The ALS Community
- Date: December 20, 2005
- Subject: Robert Packard Center ALS News Network
- http://www.alscenter.org/news/briefs/051220.cfm
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, which are described in this month's issue of Nature Neuroscience [available online 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 earlier novel studies where only some mouse cells carried 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' SOD1 is normal. And, conversely, having neighbors with mutant SOD1 can trip motor neuron death even if the motor neurons themselves have the healthy version. Other Packard scientists has confirmed the unusual results that point to the importance of a motor neuron's surroundings 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. It can also rouse nearby immune cells, the microglia, which themselves release neuron-harming agents.
The team's studies began with a fishing expedition of sorts, using a yeast two-hybrid approach, a modern technique that uses a cell protein as "bait" to see what other molecules associate with it. Mutant SOD1 was consistently linked with chromogranins - molecules closely tied to cell-secretion systems. In both nerve-cell cultures and in the spinal cords of the model mice, the team observed mutant SOD1 - but not normal SOD1 - paired with chromogranins, Further, the scientists found the pairings throughout a cell's secretory machinery, a "packaging" system called the trans-Golgi network. The older the mice, the more paired molecules appeared. "We believe that chromogranins chaperone the mutant SOD1, helping it through a cell's secretory pathways," says Julien.
Last, the researchers discovered that chromogranin production, and, accordingly, mutant SOD1 secretion, is dramatically stepped up in cells adjacent to motor neurons, bathing them in the misshapen molecule. "In a motor neuron that's under siege from events within," Julien says, "having toxic molecules outside may be a last straw in the cell's coping ability. All this," he says, "becomes a part of ALS pathology that hasn't been explored."
The research was supported by the Robert Packard Center for ALS Research at Johns Hopkins, the ALS Association, the Canadian Institutes of Health Research, the ALS Society of Canada, the Japan Society for the Promotion of Science and Japan Foundation for Neuroscience and Mental Health.
Scientists participating in the study are Makoto Urushitani (the first author) of Laval University and Attila Sik, Takashi Sakurai, Nobuyuki Nukina and Ryosuke Takahashi of the RIKEN Brain Science Institute in Saitama, Japan.
About The Robert Packard Center for ALS Research at Johns Hopkins www.alscenter.org
Located in Baltimore, the Robert Packard Center for ALS Research at Johns Hopkins is a collaboration of scientists worldwide, working aggressively to develop new treatments 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 from the laboratory bench to the clinic in record time.
Scientists and clinician members of the Packard Center are unsurpassed at moving drugs reliably and rapidly from preclinical experiments to human trials. They're linked, directly or indirectly, to the world's major pharmaceutical and biotechnology companies, which have both infrastructure and experience to make promising drugs into therapies.
Packard Center 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 devastating, progressive 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.
For more information about The Robert Packard Center for ALS Research at Johns Hopkins, including information on its latest research and treatment, visit www.alscenter.org