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

  • Hansen Lui (Contributor)
  • Jiasheng Zhang (Contributor)
  • Stefanie R. Makinson (Contributor)
  • Michelle K. Cahill (Contributor)
  • Kevin W. Kelley (Contributor)
  • Hsin Yi Huang (Contributor)
  • Yulei Shang (Contributor)
  • Michael C. Oldham (Contributor)
  • Lauren Herl Martens (Contributor)
  • Fuying Gao (Contributor)
  • Giovanni Coppola (Contributor)
  • Steven A. Sloan (Contributor)
  • Eileen H Bigio (Contributor)
  • Ian R. Mackenzie (Contributor)
  • William W. Seeley (Contributor)
  • Anna Karydas (Contributor)
  • Bruce Miller (Contributor)
  • Barbara Borroni (Contributor)
  • R. Ghidoni (Contributor)
  • Robert Farese (Contributor)
  • Jeanne T. Paz (Contributor)
  • Ben A. Barres (Contributor)
  • Eric J. Huang (Contributor)



Accession Number: GSE75083

GPL6885: Illumina MouseRef-8 v2.0 expression beadchip
GPL10787: Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Probe Name version)

Organism: Mus musculus

Published on 2016-03-31

Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency.

Overall Design:
Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here. For arrays from Agilent platform, there are 16 samples/experiments were carried out, and 1 sample was excluded from analysis, therefore 15 samples are represented in the records.

Name: Giovanni Coppola
Organization: UCLA
Laboratory: Neurogenetics
Deparment: Psychiatry and Neurology
Address: 1524 Gonda, 695 Charles Young Drive South Los Angeles CA 90095 USA
Phone: 310-794-4172

Organization: Illumina Inc.
Address: 9885 Towne Centre Drive San Diego CA 92121 USA
Phone: 1 800 809 4566
Date made availableNov 17 2015
PublisherGene Expression Omnibus

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