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Updated: Sep 8, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration
Guangyan Miao1, Tina M Fortier1, Haibo Liu1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Abstract:
The failure to clear dysfunctional mitochondria, cell death and inflammation have been linked in neurodegenerative disease, but their relationship and role in these conditions is not fully understood. Loss of Vps13d prevents clearance of mitochondria, and mutations in human VPS13D have been associated with neurological movement disorders. To investigate the relationship between mitochondrial health, inflammation and neurodegeneration, we created a conditional Vps13d-knockout mouse. Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration. Vacuolar protein sorting 13D (VPS13D) deficiency also caused mitochondrial ultrastructural defects and dysfunction in neurons followed by gasdermin E processing, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon response cGAMP interactor (STING) signaling, microglial activation and cell death. Gasdermin E localization with mitochondria in Vps13d-mutant neurons was required for elevated extracellular mitochondrial DNA that promoted activation of microglia. Depletion of microglia suppressed cell death and behavioral phenotypes but not mitochondrial changes in the neuron-specific Vps13d-knockout model, indicating that microglia promote cell death in this model of neurodegenerative disease.
Insights
Loss of Vps13d in neurons impairs mitochondrial clearance, triggering inflammation and neurodegeneration. Microglia activation promotes cell death, highlighting their role in neurodegenerative disease progression.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Mitochondrial dysfunction, cell death, and inflammation are implicated in neurodegenerative diseases.
- VPS13D mutations are linked to neurological movement disorders.
- The precise relationship between these factors in neurodegeneration remains unclear.
Purpose of the Study:
- To investigate the link between mitochondrial health, inflammation, and neurodegeneration.
- To elucidate the role of Vps13d in neuronal function and disease.
Main Methods:
- Created a conditional Vps13d-knockout mouse model.
- Analyzed neuronal and microglial responses to Vps13d loss.
- Assessed mitochondrial function, cell death pathways, and signaling cascades.
Main Results:
- Vps13d loss in neurons caused neurodegeneration and behavioral changes.
- VPS13D deficiency led to mitochondrial defects, gasdermin E processing, and cGAS-STING activation.
- Extracellular mitochondrial DNA released from Vps13d-mutant neurons activated microglia.
- Microglial depletion reduced cell death but not mitochondrial dysfunction.
Conclusions:
- Vps13d is crucial for maintaining mitochondrial health in neurons.
- Microglia activation, driven by mitochondrial damage, exacerbates neurodegeneration.
- Targeting microglia may offer therapeutic potential for Vps13d-related neurodegenerative conditions.
