Oct. 2, 2008

Problem in SMA May Start Before Nerve-Cell Loss

Spinal muscular atrophy (SMA), long believed to be caused by the loss of motor neurons (nerve cells that control muscle) in the spinal cord, may begin with events preceding motor neuron loss, according to a group of researchers coordinated by MDA grantee Umrao Monani at Columbia University in New York.

Monani and colleagues, who published their results Aug. 15 in Human Molecular Genetics, say the findings could have important implications for development of SMA treatments.

The underlying cause of SMA is a deficiency of the SMN (survival of motor neuron) protein. The more SMN one has, the better, with very low levels resulting in severe disease and somewhat higher levels resulting in mild disease. Until recently, the steps between SMN depletion and loss of motor neurons have remained obscure.

The new findings point to the meeting place of nerve and muscle fibers -- the neuromuscular junction -- as the first casualty in SMA, with the loss of motor neuron cell bodies coming as a later event. (Motor neurons have cell bodies in the spinal cord and long, thin fibers called axons that travel outside the cord and activate muscle fibers by sending them chemical signals.)

Working with SMA mice with varying levels of SMN and disease of varying severity, the researchers found the first detectable signs of SMA to be abnormalities at the tip of the axon as it nears the muscle fiber. In the SMA mice, clumps of cellular material accumulated in these axon tips on the nerve side of the neuromuscular junction. On the muscle side, the receptors (receivers) of the nerve signals formed abnormal clusters and didn't mature properly. The extent and severity of these defects correlated with disease severity and with SMN levels.

An analysis of diaphragm muscle tissue taken from severely affected SMA patients revealed neuromuscular junction defects similar to those seen in the SMA mice.

The researchers say their findings "warrant the search for strategies that would maintain function at the neuromuscular junctions as a means of treating the disease."