A disease of actin transport?

杨柳

Spinal muscular atrophy (SMA), a motoneuron disease that results in paralysis and death usually before age 3, is caused by loss of the SMN1 gene. But what does the established splicing function of SMN1 have to do with motoneurons? Perhaps very little, say Rossoll et al., who on page 801 show that SMN1 is part of a complex that drags ?-actin mRNA out to growth cones so that axons can grow and possibly function properly.The authors first looked at motoneuron survival in vitro. Survival of cells from a mouse SMA model was unimpaired, but axon growth, growth cone size, and axonal accumulation of actin was reduced. The SMN protein has been shown to associate with the RNA-binding protein hRNP R, and Rossoll et al. found that hRNP R associates, in turn, with ?-actin mRNA. The axonal concentration of both hRNP R and ?-actin mRNA are lost in cells lacking SMN1.1 y3 l) ?: \9 l7 ~- v0 `
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Individuals with SMA apparently live as long as they do because full-length SMN2 can carry out at least part of the essential splicing function of SMN proteins. But most SMN2 transcripts have a small deletion relative to SMN1, and thus are inactive in both splicing and axon localization functions. It is not yet clear if the localization function is the sole determinant of SMA disease, and if it is needed for transport of mRNAs other than ?-actin mRNA. But at least in theory the shortage of axonal actin could lead to deficits not just in axonal outgrowth but also in synaptic functioning. One distant option for correcting these defects might be to boost the activity of an mRNA transport component.(SMA neurons (right) have less actin.)