Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?

Abstract

Spinal muscular atrophy (SMA) is caused by reduced amounts of the ubiquitously expressed survival motor neuron protein (SMN). SMN functions in RNA metabolism, but the question of which aspect of its function is disrupted to give a motor neuron disease remains unanswered. SMN functions in the assembly of Sm proteins onto small nuclear RNAs (snRNAs) during pre-mRNA splicing. It has been suggested that SMN might have a role in the assembly of other ribonucleoprotein (RNP) complexes. SMA is caused by loss or mutation of SMN1 and retention of SMN2,leading to low SMN levels. Proteins that carry mild missense mutations complement SMN2 to restore assembly activity and give a mild phenotype. Loss of SMN in all species results in lethality, indicating that SMN has an essential function. Animal models of SMA can be created by reducing the levels of SMN. It has been proposed that reduction of SMN levels results in an alteration of the small nuclear ribonucleoprotein (snRNP) profile. This is supported by the correlation between snRNP assembly activity and SMA severity in mice; however, a clear indication of the downstream target genes that are affected is currently lacking. SMN is found in axons of cultured cells, and a second hypothesis suggests that altered mRNA transport in axons may contribute to SMA. However, a clear indication of what SMN function is disrupted to alter mRNA transport is lacking. SMN functions in the assembly of RNPs, but it remains unresolved whether it is an axonal or an snRNP component that is disrupted in SMA. Experiments showing a clear suppression of the phenotype by manipulating a particular pathway could be used to demonstrate the crucial pathway in SMA.