Related Experiment Video
Updated: Jun 22, 2025
Assay for Phosphorylation and Microtubule Binding Along with Localization of Tau Protein in Colorectal Cancer Cells
Published on: October 10, 2017
TMEM16F exacerbates tau pathology and mediates phosphatidylserine exposure in phospho-tau-burdened neurons
Mario V Zubia1,2,3,4, Adeline J H Yong2,3,4, Kristen M Holtz5
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143.
Abstract:
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.
Insights
The calcium-activated ion channel TMEM16F contributes to neurodegeneration by mediating aberrant phosphatidylserine exposure in neurons. Removing TMEM16F from neurons reduces tauopathy and microgliosis in a mouse model of Alzheimer's disease.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- TMEM16F functions as a calcium-activated ion channel and phospholipid scramblase, facilitating lipid transport across cell membranes.
- While TMEM16F's roles are known in various cell types, its function in the central nervous system and neurodegeneration is largely unexplored.
Purpose of the Study:
- To investigate the involvement of TMEM16F in brain neurodegeneration, specifically focusing on tauopathy.
Main Methods:
- Utilized the PS19 mouse model expressing human tau P301S mutation.
- Examined the effects of TMEM16F deficiency in whole mice, and specifically in neurons and microglia, on tauopathy and microgliosis.
- Assessed phosphatidylserine exposure in neurons with phospho-tau burden.
Main Results:
- Mice lacking TMEM16F showed reduced tauopathy and microgliosis.
- Neuron-specific TMEM16F deletion ameliorated pathology in PS19 mice.
- Microglia-specific TMEM16F deletion did not significantly impact tauopathy at the studied time point.
- TMEM16F was found to mediate aberrant phosphatidylserine exposure in tau-burdened neurons.
Conclusions:
- TMEM16F plays a significant role in neuronal tauopathy and associated neuroinflammation.
- Targeting TMEM16F in neurons presents a potential therapeutic strategy for neurodegenerative diseases like Alzheimer's.
