The SMOC1 proteomics network controls signaling modalities, brain homeostasis and toxicity in fly Alzheimer's disease models

We identified 25 genes from the SMOC1 network with robust evidence of interactions with either tau or Aβ toxicity in fly AD models. Consistent with its central, interconnected position within the network, dSMOC1 shows genetic interactions with at least 8 other network genes. dSMOC1 is expressed in the brain by many glia and some neurons, however, dSMOC1 protein is mainly localized around neuronal cell bodies. dSMOC1^-/- mutant flies have severe locomotor defects, reduced survival, and show cell-type specific changes in glypican expression, potentially linking the network to Wnt and TGF-β signaling. Finally, proteomics from dSMOC1^-/- fly heads show perturbations in ECM/Receptor interactions, metabolism, signaling, and proteostasis CONCLUSION: The SMOC1 protein network contains multiple proteins with links to AD, and dSMOC1 is likely a key driver of network function. Together, the genetics and proteomics data show that dSMOC1 is an important regulator of extracellular matrix function in the brain and suggest a mechanistic hypothesis where dSMOC1 fine-tunes multiple signaling modalities to regulate cellular homeostasis.