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Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation
Hansen Lui1, Jiasheng Zhang1, Stefanie R Makinson2
1Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Abstract:
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.
Insights
Progranulin deficiency in mice causes age-dependent microglial activation, leading to synaptic loss and obsessive-compulsive behaviors. Suppressing complement C1qa mitigates these neurodegenerative effects.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are crucial for brain homeostasis, but their role in neurodegeneration is debated.
- Progranulin (Grn) deficiency is linked to frontotemporal dementia (FTD), but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the role of progranulin deficiency in microglial activation and neurodegeneration.
- To elucidate the mechanisms by which Grn deficiency impacts brain function and behavior.
Main Methods:
- Transcriptome profiling of microglia from Grn-deficient mice.
- Analysis of microglial infiltration, synaptic pruning, and thalamocortical circuit activity.
- Genetic deletion of C1qa to assess its impact on Grn(-/-) phenotypes.
Main Results:
- Grn deficiency caused age-dependent upregulation of lysosomal and immune genes in microglia.
- Grn(-/-) mice exhibited increased synaptic pruning, thalamocortical hyperexcitability, and OCD-like behaviors.
- C1qa deletion reduced synaptic pruning, mitigated neurodegeneration, and improved survival in Grn(-/-) mice.
Conclusions:
- Progranulin normally suppresses aberrant microglial activation during aging.
- Complement activation and microglia-mediated synaptic pruning are key drivers of neurodegeneration in Grn deficiency.
- Targeting microglial complement pathways may offer therapeutic strategies for FTD and related disorders.
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