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

Hansen Lui, Jiasheng Zhang, Stefanie R. Makinson, Michelle K. Cahill, Kevin W. Kelley, Hsin Yi Huang, Yulei Shang, Michael C. Oldham, Lauren Herl Martens, Fuying Gao, Giovanni Coppola, Steven A. Sloan, Christine L. Hsieh, Charles C. Kim, Eileen H. Bigio, Sandra Weintraub, Marek Marsel Mesulam, Rosa V Rademakers, Ian R. MacKenzie, William W. SeeleyAnna Karydas, Bruce L. Miller, Barbara Borroni, Roberta Ghidoni, Robert V. Farese, Jeanne T. Paz, Ben A. Barres, Eric J. Huang

Research output: Contribution to journalArticle

187 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)921-935
Number of pages15
JournalCell
Volume165
Issue number4
DOIs
StatePublished - May 5 2016

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Neuronal Plasticity
Complement Activation
Microglia
Chemical activation
Networks (circuits)
Genes
Aging of materials
Frontotemporal Dementia
Grooming
Premature Mortality
Obsessive-Compulsive Disorder
Gene Expression Profiling
Thalamus
Infiltration
Innate Immunity
Synapses
Brain
Homeostasis
Up-Regulation
Phenotype

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lui, H., Zhang, J., Makinson, S. R., Cahill, M. K., Kelley, K. W., Huang, H. Y., ... Huang, E. J. (2016). Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell, 165(4), 921-935. https://doi.org/10.1016/j.cell.2016.04.001

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. / Lui, Hansen; Zhang, Jiasheng; Makinson, Stefanie R.; Cahill, Michelle K.; Kelley, Kevin W.; Huang, Hsin Yi; Shang, Yulei; Oldham, Michael C.; Martens, Lauren Herl; Gao, Fuying; Coppola, Giovanni; Sloan, Steven A.; Hsieh, Christine L.; Kim, Charles C.; Bigio, Eileen H.; Weintraub, Sandra; Mesulam, Marek Marsel; Rademakers, Rosa V; MacKenzie, Ian R.; Seeley, William W.; Karydas, Anna; Miller, Bruce L.; Borroni, Barbara; Ghidoni, Roberta; Farese, Robert V.; Paz, Jeanne T.; Barres, Ben A.; Huang, Eric J.

In: Cell, Vol. 165, No. 4, 05.05.2016, p. 921-935.

Research output: Contribution to journalArticle

Lui, H, Zhang, J, Makinson, SR, Cahill, MK, Kelley, KW, Huang, HY, Shang, Y, Oldham, MC, Martens, LH, Gao, F, Coppola, G, Sloan, SA, Hsieh, CL, Kim, CC, Bigio, EH, Weintraub, S, Mesulam, MM, Rademakers, RV, MacKenzie, IR, Seeley, WW, Karydas, A, Miller, BL, Borroni, B, Ghidoni, R, Farese, RV, Paz, JT, Barres, BA & Huang, EJ 2016, 'Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation', Cell, vol. 165, no. 4, pp. 921-935. https://doi.org/10.1016/j.cell.2016.04.001
Lui, Hansen ; Zhang, Jiasheng ; Makinson, Stefanie R. ; Cahill, Michelle K. ; Kelley, Kevin W. ; Huang, Hsin Yi ; Shang, Yulei ; Oldham, Michael C. ; Martens, Lauren Herl ; Gao, Fuying ; Coppola, Giovanni ; Sloan, Steven A. ; Hsieh, Christine L. ; Kim, Charles C. ; Bigio, Eileen H. ; Weintraub, Sandra ; Mesulam, Marek Marsel ; Rademakers, Rosa V ; MacKenzie, Ian R. ; Seeley, William W. ; Karydas, Anna ; Miller, Bruce L. ; Borroni, Barbara ; Ghidoni, Roberta ; Farese, Robert V. ; Paz, Jeanne T. ; Barres, Ben A. ; Huang, Eric J. / Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. In: Cell. 2016 ; Vol. 165, No. 4. pp. 921-935.
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AU - Kelley, Kevin W.

AU - Huang, Hsin Yi

AU - Shang, Yulei

AU - Oldham, Michael C.

AU - Martens, Lauren Herl

AU - Gao, Fuying

AU - Coppola, Giovanni

AU - Sloan, Steven A.

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AU - Kim, Charles C.

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AU - MacKenzie, Ian R.

AU - Seeley, William W.

AU - Karydas, Anna

AU - Miller, Bruce L.

AU - Borroni, Barbara

AU - Ghidoni, Roberta

AU - Farese, Robert V.

AU - Paz, Jeanne T.

AU - Barres, Ben A.

AU - Huang, Eric J.

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N2 - 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.

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