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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory
Amit U Joshi1, Paras S Minhas2, Shane A Liddelow3,4,5
1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration-one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.
Insights
Neurotoxic proteins in microglia can kill neurons and spread injury via damaged mitochondria. Inhibiting microglial mitochondrial fragmentation may offer a novel neuroprotection strategy for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Neuroinflammation
Background:
- Neurodegenerative diseases involve glia-mediated neuroinflammation, where dead neuron debris activates glial cells, potentially worsening neuronal death.
- The exact mechanisms by which glial cells propagate neuronal injury remain incompletely understood.
Purpose of the Study:
- To investigate if microglia expressing neurotoxic proteins can directly cause neuronal death.
- To determine the role of microglial mitochondria in propagating neuroinflammation and neuronal injury.
- To explore potential therapeutic targets for neurodegenerative diseases based on microglial function.
Main Methods:
- Inducing expression of neurotoxic proteins in microglia.
- Assessing direct neuronal death upon co-culture with modified microglia.
- Analyzing astrocyte activation to the A1 neurotoxic state.
- Investigating the role of microglial mitochondrial fragmentation (Fis1-mediated) and release of mitochondria into the extracellular environment.
- Quantifying the ratio of fragmented to functional mitochondria released from microglia.
Main Results:
- Expression of neurotoxic proteins in microglia alone was sufficient to trigger naive neuronal death.
- Microglia activated naive astrocytes to the A1 neurotoxic state, propagating injury.
- Release of fragmented, dysfunctional microglial mitochondria significantly mediated injury propagation.
- Fis1-mediated mitochondrial fragmentation in microglia controlled the release of damaged mitochondria and subsequent neuronal injury.
- The study identified a mechanism for propagating inflammatory response and neuronal cell death via extracellular dysfunctional mitochondria.
Conclusions:
- Microglial expression of neurotoxic proteins directly causes neuronal death and propagates injury through astrocyte activation.
- Dysfunctional microglial mitochondria released into the extracellular space are key mediators of neuroinflammation and neuronal death propagation.
- Inhibiting Fis1-mediated mitochondrial fragmentation in microglia presents a potential therapeutic strategy to prevent the release of toxic mitochondria, offering neuroprotection in neurodegenerative diseases.
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