TMEM106B regulates microglial proliferation and survival in response to demyelination.

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.

Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination.

Heterozygous mutations in the granulin (GRN) gene, resulting in the haploinsufficiency of the progranulin (PGRN) protein, is a leading cause of frontotemporal lobar degeneration (FTLD). Complete loss of the PGRN protein causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Polymorphisms in the GRN gene have also been associated with several other neurodegenerative diseases, including Alzheimer's disease (AD), and Parkinson's disease (PD). PGRN deficiency has been shown to cause myelination defects previously, but how PGRN regulates myelination is unknown. Here, we report that PGRN deficiency leads to a sex-dependent myelination defect with male mice showing more severe demyelination in response to cuprizone treatment. This is accompanied by exacerbated microglial proliferation and activation in the male PGRN-deficient mice. Interestingly, both male and female PGRN-deficient mice show sustained microglial activation after cuprizone removal and a defect in remyelination. Specific ablation of PGRN in microglia results in similar sex-dependent phenotypes, confirming a microglial function of PGRN. Lipid droplets accumulate in microglia specifically in male PGRN-deficient mice. RNA-seq analysis and mitochondrial function assays reveal key differences in oxidative phosphorylation in male versus female microglia under PGRN deficiency. A significant decrease in myelination and accumulation of myelin debris and lipid droplets in microglia were found in the corpus callosum regions of FTLD patients with GRN mutations. Taken together, our data support that PGRN deficiency leads to sex-dependent alterations in microglia with subsequent myelination defects.