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

Autor:	Zubia MV; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143.; Department of Physiology, University of California, San Francisco, CA 94143.; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.; HHMI, University of California, San Francisco, CA 94143., Yong AJH; Department of Physiology, University of California, San Francisco, CA 94143.; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.; HHMI, University of California, San Francisco, CA 94143., Holtz KM; Department of Autonomy, Skydio, San Mateo, CA 94402., Huang EJ; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143.; Department of Pathology, University of California, San Francisco, CA 94143., Jan YN; Department of Physiology, University of California, San Francisco, CA 94143.; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.; HHMI, University of California, San Francisco, CA 94143., Jan LY; Department of Physiology, University of California, San Francisco, CA 94143.; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.; HHMI, University of California, San Francisco, CA 94143.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 02; Vol. 121 (27), pp. e2311831121. Date of Electronic Publication: 2024 Jun 28.
DOI:	10.1073/pnas.2311831121
Abstrakt:	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. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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