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Qki is an essential regulator of microglial phagocytosis in demyelination
Jiangong Ren1, Congxin Dai1,2, Xin Zhou1,3
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Abstract:
The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia's phagocytic activity under demyelinating conditions.
Insights
The Quaking protein (Qki) is crucial for microglial phagocytosis in demyelinating diseases. Qki regulates genes essential for clearing myelin debris, promoting axon and oligodendrocyte health.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- The regulation of microglial phagocytosis in demyelinating diseases remains poorly understood.
- Microglia play a critical role in clearing myelin debris during demyelination.
Purpose of the Study:
- To elucidate the mechanism regulating microglial phagocytosis in demyelinating conditions.
- To investigate the role of the Quaking protein (Qki) in microglial function during demyelination.
Main Methods:
- Investigated Quaking protein (Qki) expression in mouse and human brain samples with demyelination.
- Utilized gene deletion models in microglia to assess Qki's function.
- Performed transcriptomic profiling and RNA immunoprecipitation (RIP) to identify Qki targets and mechanisms.
- Assessed microglial and macrophage phagocytic activity and myelin debris clearance.
Main Results:
- Quaking protein (Qki) expression was significantly induced by demyelination in microglia.
- Deletion of the Quaking gene (Qk) in microglia impaired myelin debris clearance and phagosome maturation gene expression.
- Qki directly interacts with mRNAs of phagocytosis-related genes, regulating their stability.
- Qki depletion and inhibition of its target Cd36 reduced phagocytic activity.
- Impaired myelin debris clearance by Qki-deficient microglia led to unresolved debris, harming axons and remyelination.
Conclusions:
- Quaking protein (Qki) is essential for microglial phagocytic activity during demyelination.
- Qki regulates the RNA stability of genes critical for phagocytosis and myelin debris clearance.
- Dysregulation of Qki contributes to impaired remyelination and axonal damage in demyelinating diseases.
