TMEM16F exacerbates tau pathology and mediates phosphatidylserine exposure in phospho- tau- burdened neurons

• 成果类型: Article
• 署名作者: Zubia, Mario V.; Yong, Adeline J. H.; Holtz, Kristen M.; Huang, Eric J.; Jan, Yuh Nung; Bcd, Lily Y. Jan
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Howard Hughes Medical Institute; University of California System; University of California San Francisco
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12580
• DOI: 10.1073/pnas.2311831121
• 发表日期: 2024-07-02
• 关键词: neurofibrillary tangles; extracellular vesicles; mouse model; protein; microglia; phosphorylation; propagation; platelets; patient; lipids

摘要

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.