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. SIGNIFICANCE STATEMENTMany ubiquitously expressed genes cause highly selective neurodegenerative diseases, such as Huntingtons disease and Amyotrophic Lateral Sclerosis. The basis for this cell-specific vulnerability remains unclear. We address this question for smn-1 in C. elegans. We show that smn-1 is indeed required in a cell-specific manner, but unexpectedly not in neurons, but rather in the intestine. Both survival defects and behavioral phenotypes originate from intestinal loss of smn-1. We show that these defects are caused by hyperactive protein degradation and immune responses, and that mutant defects can be resolved by reducing these proteostasis and immune pathways using genetics or pharmacology. These results shed light on how a single tissue/cell can dictate the effects of a systemic genetic disease.