Multifaceted roles of the lipid scramblase TMEM16F in tauopathy

TMEM16F is a calcium-activated phospholipid scramblase and non-selective ion channel, which can move lipids bidirectionally across the plasma membrane. While earliest studies of TMEM16F have implicated its function in the release of microvesicles, large extracellular vesicles budded directly from the plasma membrane, we have found that knockout of TMEM16F from microglia additionally results in increased release of exosomes, extracellular vesicles derived from exocytosis of multivesicular bodies. Microglial exosomes have been implicated in the spread of soluble tau oligomers in the P301S mouse model of tauopathy. We sought to investigate the pathological effect of increased microglial exosomes from TMEM16F knockout in these tauopathy mice. When TMEM16F was removed from microglia, we observed worsening of hyperphosphorylated tau and microgliosis, suggesting an increase in exosomes can contribute towards pathology. However, when TMEM16F was knocked out from all cells, we found the opposite phenotype, with knockout mice having a reduction in pathology compared to those with TMEM16F intact. In P301S mice, neurons have been shown to aberrantly expose phosphatidylserine (PS), targeting them for premature death by microglia. Thus, we investigated if neurons with pathological tau burden and removal of TMEM16F still experienced this PS exposure and whether a deficiency in PS exposure may explain the reduction in pathology. In vitro cultures of tau burdened TMEM16F knockout neurons exposed less PS and had fewer interactions with WT microglia that were added to the neuronal cultures. These findings suggest TMEM16F may become activated in neurons with tauopathy to expose PS while TMEM16F in microglia may influence the balance of microvesicle and exosome release. Better understanding of TMEM16F may facilitate its manipulation in various cell types toward future development of therapeutics