Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Significance Spinal muscular atrophy (SMA), a common genetic motor neuron (MN) degenerative disease and leading hereditary cause of infant mortality, results from survival of motor neuron (SMN) protein deficiency. However, SMN’s ubiquitous expression and housekeeping functions in biogenesis of snRNPs, the spliceosome’s subunits, seems difficult to reconcile with SMA’s MN selective pathology. Here, we sequenced transcriptomes of MNs and adjacent white matter microdissected from spinal cords of presymptomatic SMA mice. This process revealed selective and MN-specific splicing and expression-level perturbations of mRNAs, including those essential for establishing neuromuscular junctions, the first structures that degenerate in SMA. We suggest that SMN’s central role in transcriptome regulation explains the gene-expression perturbations that impair MN function and survival in SMA.