The mutation that causes a motor neuron degenerative disease also produces defects in basic cellular machinery.

Spinal muscular atrophy causes motor neurons, shown here as they connect to skeletal muscle, to degenerate.

Spinal muscular atrophy—a degeneration of motor neurons that causes muscle wasting—stems from mutations in a protein called “survival of motor neurons” (SMN). SMN does more than just keep motor neurons alive and functioning; it is vital in every cell in the body for splicing unneeded genetic bits out of RNA after it is copied from its DNA blueprint. SMN's task is to construct small RNA-protein complexes, known as small nuclear RNA ribonucleoproteins (snRNPs)—the building blocks of the cell's splicing apparatus (the “spliceosome”).

Since all cells need this housekeeping activity, it's been a mystery why mutations in SMN affect only motor neurons. Now, researchers have discovered clues to the mechanism that allows the mutation to have varied responses in different tissues.

When they engineered cultured human cells with reduced SMN levels, researchers led by HHMI investigator Gideon Dreyfuss of the University of Pennsylvania School of Medicine found that not all the snRNPs were affected in the same way. “Rather than a uniform decrease in the levels of all the snRNPs, some were more affected than others,” says Dreyfuss.

To explore whether this varied response might affect tissues in different ways, the researchers turned to SMN-deficient mice.

“We found a different snRNP repertoire change in every tissue we looked at,” says Dreyfuss.

When the scientists looked at how RNA was spliced in these mice, they also found tissue differences. “The abnormalities we saw told us clearly there is something aberrant about the splicing process,” explains Dreyfuss. “Not only did we see basic splicing defects, we also saw spliced RNA forms never before detected in normal mice in any tissue.”

The results, which appear in the May 16, 2008, issue of Cell, don't answer why motor neurons are affected so drastically, but they do reveal that SMN is a key orchestrator of the splicing process and illustrate how different tissues respond in a unique way to mutations in a protein needed by all. Knowing that patients with spinal muscular atrophy have spliceosome defects in more than just neural cells, Dreyfuss says, suggests that future therapies should target the whole body.

Photo: Kent Wood / Photo Researchers, Inc