TMEM16F is a calcium-activated phospholipid scramblase and nonselective ion channel, which allows the movement of lipids bidirectionally across the plasma membrane. While the functions of TMEM16F have been extensively characterized in multiple cell types, the role of TMEM16F in the central nervous system remains largely unknown. Here, we sought to study how TMEM16F in the brain may be involved in neurodegeneration. Using a mouse model that expresses the pathological P301S human tau (PS19 mouse), we found reduced tauopathy and microgliosis in 6- to 7-mo-old PS19 mice lacking TMEM16F. Furthermore, this reduction of pathology can be recapitulated in the PS19 mice with TMEM16F removed from neurons, while removal of TMEM16F from microglia of PS19 mice did not significantly impact tauopathy at this time point. Moreover, TMEM16F mediated aberrant phosphatidylserine exposure in neurons with phospho-tau burden. These studies raise the prospect of targeting TMEM16F in neurons as a potential treatment of neurodegeneration.

中文翻译：

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TMEM16F 加剧 tau 病理学并介导磷酸 tau 神经元中磷脂酰丝氨酸的暴露


TMEM16F 是一种钙激活的磷脂扰乱酶和非选择性离子通道，允许脂质在质膜上双向移动。虽然 TMEM16F 的功能已在多种细胞类型中得到广泛表征，但 TMEM16F 在中枢神经系统中的作用仍然很大程度上未知。在这里，我们试图研究大脑中的 TMEM16F 如何参与神经退行性变。使用表达病理性 P301S 人类 tau 蛋白的小鼠模型（PS19 小鼠），我们发现缺乏 TMEM16F 的 6 至 7 个月大的 PS19 小鼠中 tau 蛋白病和小胶质细胞增生减少。此外，这种病理学的减少可以在从神经元中去除 TMEM16F 的 PS19 小鼠中重现，而从 PS19 小鼠的小胶质细胞中去除 TMEM16F 在这个时间点并没有显着影响 tau 蛋白病。此外，TMEM16F 介导具有磷酸 tau 负荷的神经元中异常的磷脂酰丝氨酸暴露。这些研究提出了以神经元中的 TMEM16F 为靶点作为神经退行性疾病潜在治疗方法的前景。