Hyperactive intestinal proteolysis underlies smn-1 mutant phenotypes

Many neurological diseases are caused by mutations in broadly-expressed genes, but the basis for their neuron-specific manifestation is unclear. In Spinal Muscular Atrophy (SMA), loss of the ubiquitously-expressed spliceosome assembly factor SMN1 causes selective degeneration of motor neurons, leading to progressive neuromuscular decline. We explored the mechanisms of this cell-specific vulnerability using SMA models in the nematode C. elegans , which likewise exhibit progressive neuromuscular defects upon loss of smn-1 . Surprisingly, our results show that the intestine – not neurons or muscle – is the selectively-vulnerable tissue causing smn-1 phenotypes. RNA-Seq reveals that loss of intestinal smn-1 causes specific global splicing defects, accompanied by robust transcriptional activation of the Intracellular Pathogen Response (IPR), a stress pathway enriched for ubiquitin-proteostasis genes. Consistent with this, smn-1 mutants exhibit elevated levels of proteasome activity. Pharmacological proteasome inhibition rescues many of the smn-1 mutant defects, as does deletion of specific components of the IPR pathway. These results reveal how the ubiquitously-expressed SMN-1 protein is required in a single tissue to avoid degenerative defects caused by hyperactive proteasome activity, contributing to our understanding of how mutations in ubiquitously-expressed genes can cause highly cell-specific pathologies.