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Abstract
Neurodegenerative diseases affect millions of people worldwide and are the leading cause of disability in older adults. Chronic neuroinflammation is an underlying mechanism for the initiation and progression of many neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. One of the key drivers of inflammatory response in the central nervous system is chronic activation of microglia cells. Activated microglia produce several neurotoxic factors, including prostaglandins, pro-inflammatory cytokines, and reactive oxygen species. Therefore, anti-inflammatory mechanisms that regulate microglia activation are therapeutic targets for neurodegenerative diseases. The Regulator of G protein signaling 10 (RGS10) is expressed in microglia, and loss of its expression during inflammation is associated with dysregulation of the microglial pro-inflammatory response and an increased risk of age-related neurodegeneration. However, the anti-inflammatory effect of RGS10 is mediated by an unknown mechanism, independent of its canonical role in G protein regulation. Therefore, while the protective functions of RGS10 position it as an anti-inflammatory target for neurodegenerative diseases, the lack of information on its molecular mechanism limits its therapeutic potential. In this study, we used a combination of proteomics and signaling approaches and identified a biochemical and functional interaction between RGS10 and the endoplasmic reticulum (ER)-localized calcium sensor STIM2, which is an essential component of the store-operated calcium entry (SOCE) machinery. Furthermore, we determined that the SOCE pathway is required for the induction of pro-inflammatory genes in microglia and that the anti-inflammatory effects of RGS10 require a functional interaction with the SOCE machinery. In addition to its anti-inflammatory role, transcriptome analysis showed that RGS10 regulates a wide range of genes involved in stress response pathways and innate immune and viral defense processes, further suggesting additional neuroprotective functions. Overall, our study provides information on the protective mechanisms of RGS10, which has implications for many neurodegenerative diseases associated with chronic neuroinflammation.