GSE128129
Multi-omic analysis identifies APC/C-mediated degradation of SMN in neurons
Spinal muscular atrophy (SMA) due to loss-of-function of SMN protein is associated with severe loss of voluntary muscle control and is a leading inherited cause of infant mortality. SMA treatments will benefit from in-depth knowledge of functional pathways disrupted in disease and identification of SMN modulators. Here, we present a comprehensive temporal profile of proteogenomic expression patterns in developing mouse spinal cords (?7 model), alongside endpoint analyses of human spinal and ventral root tissues in SMA disease, identifying targets for assessing disease progression and treatment response. SMA disease results in development-associated deficiencies in transcription, translation initiation, intracellular transport, and protein folding, and diminished RNA translation efficiency for proteins important in axon development/myelination. The broad impact of SMN deficiency prompted the search for co-regulated proteins that modulate SMN protein levels, resulting in identification of the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin ligase as a potential modulator of SMN protein stability. Functional studies of APC/C showed that both SMN and HuD are specific interactors of the APC/C in neurons and that selective APC/C inhibition significantly limited SMN and HuD degradation. Finally, we demonstrate that APC/C inhibition rescues motor axon defects characteristic of SMA in a zebrafish model of SMA disease. Overall design: Total RNA was extracted from whole P2, P6, and P10 homozygote (SMA) or heterozygote (control) murine spinal cords (SMN?7 mouse model) for RNAseq comparison.