Scientists Take Big Step Toward Explaining Cause of Spinal Muscle Atrophy

Scientists at the Johns Hopkins School of Public Health are getting closer to explaining how spinal muscular atrophy (SMA), the most common genetic cause of death in children, destroys motor neurons in the spinal cord. The study appeared in the November 21, 2000 issue of the Proceedings of the National Academy of Sciences.

More than 96 percent of patients with SMA have a mutation in a common protein, the survival motor neuron (SMN) protein, and the current study now shows that this mutated form of SMN can itself destroy neurons.

Most cells are normally programmed to die at specific stages and sites during their development, a natural and necessary process known as apoptosis. The present study is the first to reveal that SMN protein is a regulator of apoptosis. The researchers found that, while SMN from healthy individuals ordinarily protects neurons from damaging insults, if the damage becomes too great, as during a stroke, then the SMN protein can become harmful.

The scientists found that during a stroke, for instance, SMN can be snipped into two pieces, and that one of the two fragments actually encourages neurons to die prematurely. The study also found a crucial connection: The harmful snippet of SMN mimics the genetically mutated protein found in children with spinal muscular atrophy.

"We've found that, whereas normal full-length SMN protects against programmed motor neuron death, the mutated SMN from patients with spinal muscular atrophy -- as well as the SMN fragment found in animals with stroke -- actually increases apoptosis and mortality," said senior author J. Marie Hardwick, PhD, professor, Molecular Microbiology and Immunology, Johns Hopkins School of Public Health. "In other words, our results suggest that SMN may be converted from a factor that protects neurons from apoptosis into a killer factor."

According to co-investigator Douglas Kerr, MD, PhD, assistant professor, Neurology, Johns Hopkins School of Medicine, understanding how SMN changes from a protector to a killer should provide potential targets for treating spinal muscle atrophy.

To find out how the SMN protein regulates neuronal apoptosis, the researchers infected neurons of the brain and spinal cord of mice with Sindbis virus (SV) that was carrying copies of normal or mutated SMN. Using an electron microscope, the researchers generated images of the neurons and, as they had hypothesized, determined that the neurons having normal full-length SMN were healthy, but that those with truncated or mutated SMN displayed the classic features of neuronal apoptosis.

The researchers said further studies are needed to determine whether the mutated short form of SMN actively destroys motor neurons or simply interferes with the protective role of full-length SMN.

This work was supported by grants from the Muscular Dystrophy Association, the Parkinson Disease Foundation, and the National Institutes of Health.