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 Rademakers; Ian R. MacKenzie; William W. Seeley; Anna Karydas; Bruce L. Miller; Barbara Borroni; Roberta Ghidoni; Robert V. Farese; Jeanne T. Paz; Ben A. Barres; Eric J. Huang

doi:10.1016/j.cell.2016.04.001

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 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

503 Scopus citations

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 language	English (US)
Pages (from-to)	921-935
Number of pages	15
Journal	Cell
Volume	165
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2016.04.001
State	Published - May 5 2016

Funding

We thank Ivy Hsieh for immunogold EM, Eric Bennett, Jordan Sorokin, and John Huguenard for their feedback on the Matlab code for analyzing the multi-unit recording in the thalamus, and Dr. Jennifer Cotter for critical comments on the manuscript. This work has been supported by NIH AG013854 (E.H.B.), P50 AG023501 and P01 AG019724 (B.L.M. and W.W.S.), P30 AI027763 and P30 DK063720 (C.C.K.), Italian Ministry of Health (Ricerca Corrente, R.G.), JPB Foundation (B.A.B.), Department of Veterans Affairs Career Development Award-2 (C.L.H.), Merit Awards BX002690 (C.L.H.) BX001108 (E.J.H.), and RX002133 (E.J.H.), and Consortium for Frontotemporal Dementia Research (CFR) and the Bluefield Project (B.L.M, W.W.S., and E.J.H.). Special thanks to Dr. Laura Mitic and Dr. Rodney Pearlman for their unwavering support. We thank Ivy Hsieh for immunogold EM, Eric Bennett, Jordan Sorokin, and John Huguenard for their feedback on the Matlab code for analyzing the multi-unit recording in the thalamus, and Dr. Jennifer Cotter for critical comments on the manuscript. This work has been supported by NIH AG013854 (E.H.B.), P50 AG023501 and P01 AG019724 (B.L.M. and W.W.S.), P30 AI027763 and P30 DK063720 (C.C.K.), Italian Ministry of Health (Ricerca Corrente, R.G.), JPB Foundation (B.A.B.), Department of Veterans Affairs Career Development Award-2 (C.L.H.), Merit Awards BX002690 (C.L.H.) BX001108 (E.J.H.), and RX002133 (E.J.H.), and Consortium for Frontotemporal Dementia Research (CFR) and the Bluefield Project (B.L.M, W.W.S., and E.J.H.). Specia

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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Lui, H., Zhang, J., Makinson, S. R., Cahill, M. K., Kelley, K. W., Huang, H. Y., Shang, Y., Oldham, M. C., Martens, L. H., Gao, F., Coppola, G., Sloan, S. A., Hsieh, C. L., Kim, C. C., Bigio, E. H., Weintraub, S., Mesulam, M. M., Rademakers, R., MacKenzie, I. R., ... 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

@article{d8ec81a4fb984455bfd3b55ee50b2431,

title = "Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = may,

day = "5",

doi = "10.1016/j.cell.2016.04.001",

language = "English (US)",

volume = "165",

pages = "921--935",

journal = "Cell",

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number = "4",

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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, R, 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

TY - JOUR

T1 - Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

AU - Lui, Hansen

AU - Zhang, Jiasheng

AU - Makinson, Stefanie R.

AU - Cahill, Michelle K.

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.

AU - Hsieh, Christine L.

AU - Kim, Charles C.

AU - Bigio, Eileen H.

AU - Weintraub, Sandra

AU - Mesulam, Marek Marsel

AU - Rademakers, Rosa

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.

PY - 2016/5/5

Y1 - 2016/5/5

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.

AB - 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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AN - SCOPUS:84963969178

SN - 0092-8674

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JO - Cell

JF - Cell

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ER -

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

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