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Glial cells are early sensors of neuronal injury and can store lipids in lipid droplets under oxidative stress conditions. Here, we investigated the functions of the RNA-binding protein,  SPEN/SHARP,  in the context of Parkinson’s disease (PD). Using a data-mining approach, we found that  SPEN/SHARP  is one of many astrocyte-expressed genes that are significantly differentially expressed in the  substantia nigra  of PD patients compared with control subjects. Interestingly, the differentially expressed genes are enriched in lipid metabolism-associated genes. In a  Drosophila  model of PD, we observed that flies carrying a loss-of-function allele of the ortholog  split-ends  ( spen ) or with glial cell-specific, but not neuronal-specific,  spen  knockdown were more sensitive to paraquat intoxication, indicating a protective role for Spen in glial cells. We also found that Spen is a positive regulator of Notch signaling in adult  Drosophila  glial cells. Moreover, Spen was required to limit abnormal accumulation of lipid droplets in glial cells in a manner independent of its regulation of Notch signaling. Taken together, our results demonstrate that Spen regulates lipid metabolism and storage in glial cells and contributes to glial cell-mediated neuroprotection.

Spen modulates lipid droplet content in adult Drosophila glial cells and protects against paraquat toxicity