Jablonka et al.
The paralysis that occurs in patients with spinal muscular atrophy (SMA) stems from defective SMN1, a protein that interacts with mRNA transport factors. Motoneurons seem to be particularly sensitive to the transport problems, perhaps due to their considerable length. In mice with mutant SMN1, β-actin mRNA is not brought correctly to axonal tips, where it normally forms scaffolds needed for vesicle trafficking to the presynaptic membrane.
The scarcity of β-actin scaffolds, the team now shows, severely hinders the delivery of calcium channels to the membrane. Without the usual dense clusters of these channels, calcium influx and thus neuronal excitation were impaired. The excitation defects could be reversed by stimulating the production of SMN protein from a relative of the SMN1 gene, called SMN2.
Although motoneurons die off in SMA, previous analysis of a mouse model indicated that the disease manifested before this death. The findings from Jablonka et al. confirm that it's not motoneuron death that's to blame and suggest instead that the problem is a lack of motoneuron function. Restoring presynaptic calcium channel clustering and neuronal firing might be a promising therapeutic avenue.