AbstractMicroglia play an important protective role in the healthy nervous tissue, being able to react to a variety of stimuli that induce different intracellular cascades for specific tasks. Ca²⁺ signaling can modulate these pathways, and we recently reported that microglial functions depend on the endoplasmic reticulum as a Ca²⁺ store, which involves the Ca²⁺ transporter SERCA2b. Here, we investigated whether microglial functions may also rely on the Golgi, another intracellular Ca²⁺ store that depends on the secretory pathway Ca²⁺/Mn²⁺‐transport ATPase isoform 1 (SPCA1). We found upregulation of SPCA1 upon lipopolysaccharide stimulation of microglia BV2 cells and primary microglia, where alterations of the Golgi ribbon were also observed. Silencing and overexpression experiments revealed that SPCA1 affects cell morphology, Golgi apparatus integrity, and phagocytic functions. Since SPCA1 is also an efficient Mn²⁺ transporter and considering that Mn²⁺ excess causes manganism in the brain, we addressed the role of microglial SPCA1 in Mn²⁺ toxicity. Our results revealed a clear effect of Mn²⁺ excess on the viability and morphology of microglia. Subcellular analysis showed Golgi fragmentation and subsequent alteration of SPCA1 distribution from early stages of toxicity. Removal of Mn²⁺ by washing improved the culture viability, although it did not effectively reverse Golgi fragmentation. Interestingly, pretreatment with curcumin maintained microglia cultures viable, prevented Mn²⁺‐induced Golgi fragmentation, and preserved SPCA Ca²⁺‐dependent activity, suggesting curcumin as a potential protective agent against Mn²⁺‐induced Golgi alterations in microglia.