The SMOC1‐matrisomal proteomics network M42 controls brain homeostasis and modulates toxicity in fly Alzheimer’s Disease models

Abstract

AbstractBackgroundRecent evidence indicates Alzheimer’s disease (AD) has a complex etiology where insults in multiple pathways collude to disrupt neuronal function, yet the molecular changes underlying AD remain poorly understood. To identify changes associated with AD, we previously performed mass‐spectrometry (MS) on post‐mortem brain tissue and identified protein co‐expression networks correlated to AD pathological and clinical traits. The network most strongly correlated with AD pathology (M42) is enriched in components of the matrisome and consists of 32 proteins including multiple signaling pathways, Aß, APOE, and SMOC1, a predicted driver of network behavior. SMOC1 is a key matrisomal protein with conserved roles in modulating TGF‐Beta and wnt signaling during development, yet its role in the adult brain remains unstudied.MethodsWe evaluate the M42 protein network using the powerful genetics of Drosophila melanogaster to determine its role in the brain and uncover links to specific triggers of AD: Amyloid‐Beta (Aβ) and tau. We use a high‐throughput robotic screening platform and video assisted software which enables quantitative assessments of neurological function to identify proteins that modify Aβ‐ or tau‐induced neurodegeneration. We use Mass‐Spectrometry to identify protein changes in the brains of flies harboring homozygous loss‐of‐function mutations in dSMOC1 and genetics, cell biology, and immunofluorescence to characterize dSMOC1 in the fly.ResultsWe identified 13 genes with robust evidence of interactions with either tau or Aβ toxicity including dSMOC1 and multiple signaling components. We focused on dSMOC1, finding that flies homozygous for null mutations (dSMOC1−/−) suffer severely decreased survival upon aging. In the fly brain, dSMOC1 is expressed primarily in glia while the protein is localized around most neuronal cell bodies, consistent with its matrisomal role. Finally, we determined protein changes in the brain of dSMOC1−/− flies and found that ECM/receptor interactions and many metabolic pathways including KREBs/TCA cycle, lipid metabolism, and Oxidative Phosphorylation were perturbed.ConclusionThe M42 protein co‐expression network contains multiple proteins with links to AD. We identified multiple conserved M42 member proteins interacting with specific AD triggers. Together, the genetics and proteomics data support a mechanistic hypothesis where changes in SMOC1 levels disrupt critical signaling pathways leading to disruptions in metabolism affecting survival.