Research Update

The Enemy Without
New evidence that what’s outside motor neurons could be the last straw

Not long ago, some intricate studies by Packard scientists Don Cleveland, Larry Goldstein and Jean-Pierre Julien showed that whatever pushes motor neurons to their death in ALS probably comes from outside those very cells. The researchers’ findings from an unusual set of ALS mice and rats—crazy-quilt animals engineered so some of their cells carry genes for the disease and some don’t—made it clear that a motor neuron’s environment might be all-important in determining whether it succumbs.

“Are chromogranins part of sporadic ALS? We’ll find out,” says Julien.

Now new work by Julien’s Canadian team adds weight to that idea while it suggests how things might go wrong. The studies, published in January’s Nature Neuroscience, describe how mutant SOD1, the molecule underlying certain familial forms of ALS, is secreted into a motor neuron’s environment, where it harms that cell.

The work began at Laval University in Quebec, where the scientists conducted a fishing expedition of sorts using the yeast two-hybrid approach—a modern technique that makes one cell protein into bait to see what others it attracts. They found that within cells of animal ALS models, mutant SOD1 was consistently linked with chromogranins, complex protein molecules that participate in cell secretion.

A vesicle holding mutant SOD1 (black spots) makes its way to a cell’s membrane.

In cultures of nerve cells as well as in the spinal cords of ALS mice, the team observed mutant SOD1—but not normal SOD1—and chromogranin pairs. The older the mice, the more pairs they had. Further, they found that the pairings settled throughout a cell’s secretory machinery, a packaging system called the trans-Golgi network. In cells that secrete substances, chiefly neurons and those of endocrine glands, large, material-filled storage vesicles form within the Golgi’s narrow channels. The vesicles migrate to a cell’s outer membrane, fuse with it and release their contents outside.

“We came to believe that chromogranins act like chaperones,” says Julien, “that they help secretion of the mutant, misfolded SOD1.”

Last, the scientists discovered that chromogranin production, and, accordingly, the release of mutant SOD1, is dramatically stepped up in cells adjacent to motor neurons, tainting the area with the misshapen molecule. “In a motor neuron already under siege from events within,” says Julien, “having toxic molecules outside may be a last straw in its coping ability.” In neural cultures they studied, Julien says, mutant SOD1 outside of motor neurons is directly toxic to them.

Moreover, nearby immune cells, the microglia, are activated by mutant SOD1, the team found, and the resulting inflammation adds to motor neuron harm. All this,” Julien explains, “becomes a part of ALS pathology we haven’t explored.”

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