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Cell. 2016 May 5;165(4):921-35. doi: 10.1016/j.cell.2016.04.001. Epub 2016 Apr 21.

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Author information

1
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
5
FORUM Pharmaceuticals, Waltham, MA 02451, USA.
6
Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, CA 90095, USA.
7
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
8
Immunology Section, San Francisco VA Medical Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94121, USA.
9
Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
10
Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
11
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
12
Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada.
13
Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
14
Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia 25100, Italy.
15
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia 25100, Italy.
16
Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, MA 02115, USA.
17
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Pathology Service (113B), San Francisco VA Medical Center, San Francisco, CA 94121, USA. Electronic address: eric.huang2@ucsf.edu.

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.

PMID:
27114033
PMCID:
PMC4860138
DOI:
10.1016/j.cell.2016.04.001
[Indexed for MEDLINE]
Free PMC Article

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