TMEM106B regulates microglial proliferation and survival in response to demyelination
Tingting Zhang1, Weilun Pang1, Tuancheng Feng1
1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
Abstract:
TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the TMEM106B risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.
Insights
Transmembrane protein 106B (TMEM106B) deficiency impairs microglia function and survival, impacting brain myelination. This study reveals TMEM106B
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Transmembrane protein 106B (TMEM106B) is linked to brain health.
- The role of TMEM106B in regulating neuroinflammation is not well understood.
Purpose of the Study:
- To investigate the function of TMEM106B in microglial responses during demyelination.
- To elucidate the molecular mechanisms by which TMEM106B influences microglial activity and survival.
Main Methods:
- Utilizing TMEM106B-deficient mouse models.
- Analyzing microglial proliferation, activation, apoptosis, lysosomal function, and TREM2 expression.
- Investigating the impact of TMEM106B ablation specifically in microglia.
- Correlating TMEM106B genetic variants with human neuroimaging and cell count data.
Main Results:
- TMEM106B deficiency reduces microglia proliferation and activation while increasing apoptosis during demyelination.
- Loss of TMEM106B leads to impaired lysosomal pH and decreased lysosomal enzyme activity in microglia.
- TMEM106B deficiency significantly downregulates TREM2 protein levels.
- Specific deletion of TMEM106B in microglia recapitulates these phenotypes and causes myelination defects.
- Human genetic data show an association between TMEM106B risk alleles, myelin loss, and reduced microglial numbers.
Conclusions:
- TMEM106B is crucial for maintaining microglial functionality, including survival, proliferation, and activation, particularly under demyelination conditions.
- TMEM106B regulates lysosomal homeostasis and TREM2 expression in microglia, which are vital for their immune functions.
- Microglial TMEM106B plays a critical role in the myelination process.
- Genetic variations in TMEM106B impact human brain myelination and microglial populations.
