Related Experiment Video
Updated: May 26, 2025
Two-photon Imaging of Microglial Processes' Attraction Toward ATP or Serotonin in Acute Brain Slices
Published on: January 31, 2019
GPNMB and ATP6V1A interact to mediate microglia phagocytosis of multiple types of pathological particles
Mei Liu1, Jianping Zhu1, Jiawei Zheng2
1Guangdong Province Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Abstract:
Pronounced elevation of glycoprotein non-metastatic melanoma B (GPNMB) is a common phenomenon in a variety of brain diseases, but the expression patterns, functions, and molecular signaling of GPNMB have not been well studied. Here, we showed that pathological factors, including neuronal degeneration caused by seizures, caspase-3-induced neuronal apoptosis, neuronal debris, and β-amyloid, induced "on-demand" GPNMB expression in hippocampal microglia. Genetic ablation of GPNMB did not affect acute seizures but worsened chronic epileptogenesis. We found that GPNMB functioned in phagocytosis, deficiency of which resulted in defects in both phagocytic engulfment and degradation. GPNMB could be internalized into cells, where it wrapped engulfed pathogenic particles and presented them to lysosomes through interaction with lysosomal vacuolar-type proton ATPase catalytic subunit A (ATP6V1A). Activating ATP6V1A was able to rescue GPNMB-deficiency-caused phagocytosis impairment. Thus, microglial GPNMB-ATP6V1A might be a common treatment target of a batch of chronic neurological disorders, and clearing the degenerative neurons might be more valuable than reserving them to protect the brain.
Insights
Glycoprotein non-metastatic melanoma B (GPNMB) in microglia aids in clearing brain debris. Enhancing its pathway may treat chronic neurological disorders by improving phagocytosis.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Glycoprotein non-metastatic melanoma B (GPNMB) is elevated in various brain diseases, yet its precise roles and signaling pathways remain unclear.
- Understanding GPNMB's function in microglia is crucial for developing treatments for neurological conditions.
Purpose of the Study:
- To investigate the expression patterns, functions, and molecular mechanisms of GPNMB in the context of brain pathology.
- To determine the role of GPNMB in microglial response to neurodegenerative conditions and seizures.
Main Methods:
- Induction of GPNMB expression in hippocampal microglia by pathological factors (neuronal degeneration, apoptosis, beta-amyloid).
- Genetic ablation of GPNMB in a mouse model to assess its impact on seizures and epileptogenesis.
- Analysis of GPNMB's function in phagocytosis and its interaction with cellular components like ATP6V1A.
Main Results:
- Pathological stimuli trigger "on-demand" GPNMB expression in hippocampal microglia.
- GPNMB deficiency exacerbates chronic epileptogenesis but does not affect acute seizures.
- GPNMB is essential for efficient microglial phagocytosis, interacting with ATP6V1A to facilitate the degradation of engulfed material.
Conclusions:
- Microglial GPNMB plays a critical role in clearing pathological debris and may be a therapeutic target for chronic neurological disorders.
- The GPNMB-ATP6V1A pathway is vital for microglial phagocytic function.
- Clearing degenerating neurons may be a more effective neuroprotective strategy than preserving them.
Related Concept Videos
01:17Phagocytosis of Apoptotic Cells
Normal cells contain receptors that prevent them from being recognized...
01:25Immune Surveillance by NK Cells and Phagocytes
Natural Killer Cells: The Fast Responders
NK cells are large granular lymphocytes found in the blood and lymphatic system. These...