SOD1 Mutations Kill Nerve Cells - With Help

Since 1993, ALS researchers have known that about 2 percent of ALS cases result from a mutation of the gene for superoxide dismutase 1 (SOD1), but the mechanism by which the mutated gene and the resulting abnormal SOD1 protein molecules kill motor neurons (nerve cells that control muscles) in this disease has so far eluded them.

Now, scientists at Laval University in Quebec and Riken Brain Science Institute in Wako City, Japan, may be closing in on an answer.

Makoto Urushitani and Jean-Pierre Julien at Laval University, and colleagues, who published their results in the January issue of Nature Neuroscience, say that, in the SOD1 form of ALS, motor neurons and probably other cells in the vicinity secrete abnormal SOD1 (from mutated SOD1 genes) in the company of proteins known as chromogranins.

Normal SOD1 protein molecules are also secreted by nerve cells, the investigators say, but without chromogranins. In fact, the secretion of normal SOD1 from cells may protect the area from potentially hostile conditions. But the combination of abnormal (improperly folded) mutant SOD1 proteins and chromogranins apparently leads to inflammation and cell death by activating the local immune system.

“Chromogranins may act like chaperones that accompany misfolded proteins when they’re secreted,” says MDA-funded neurologist Stanley Appel, who directs the MDA/ALS Center at the Methodist Neurological Institute in Houston.

Appel calls the new study significant and says it suggests that the abnormal SOD1 may activate microglia, the immunoactive scavengers of the central nervous system, causing them to attack and kill motor neurons.

He believes there may be similar immunologic triggers present in non-SOD1 forms of ALS. “The process of interacting with microglia could be comparable,” Appel says.

“You just have to change the name of the player. We know the name of the player in one form of ALS; it’s SOD1. But any protein can look unusually unique to the immune system, because of a genetic mutation or a viral disease or for other reasons. There may be one altered protein in one patient and another in another patient.”