The intriguing case of motor neuron disease: ALS and SMA come closer

MNDs (motor neuron diseases) form a heterogeneous group of pathologies characterized by the progressivedegeneration of motor neurons. More and more genetic factors associated with MND encode proteinsthat have a function in RNA metabolism, suggesting that disturbed RNA metabolism could be a commonunderlying problem in several, perhaps all, forms of MND. In the present paper we review recentdevelopments showing a functional link between SMN (survival of motor neuron), the causative factorof SMA (spinal muscular atrophy), and FUS (fused in sarcoma), a genetic factor in ALS (amyotrophic lateralsclerosis). SMN is long known to have a crucial role in the biogenesis and localization of the spliceosomalsnRNPs (small nuclear ribonucleoproteins), which are essential assembly modules of the splicing machinery.Now we know that FUS interacts with SMN and pathogenic FUS mutations have a significant effect on snRNPlocalization. Together with other recently published evidence, this finding potentially links ALS pathogenesisto disturbances in the splicing machinery, and implies that pre-mRNA splicing may be the common weakpoint in MND, although other steps in mRNA metabolism could also play a role. Certainly, further comparisonof the RNA metabolism in different MND will greatly help our understanding of the molecular causes ofthese devastating diseases. © 2013 Biochemical Society.