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

被引：547

作者：

Lui, Hansen ^{[1
,21
]}

Zhang, Jiasheng ^{[1
]}

Makinson, Stefanie R. ^{[2
,3
]}

Cahill, Michelle K. ^{[1
]}

Kelley, Kevin W. ^{[4
]}

Huang, Hsin-Yi ^{[1
,22
]}

Shang, Yulei ^{[1
]}

Oldham, Michael C. ^{[5
]}

Martens, Lauren Herl ^{[6
]}

Gao, Fuying ^{[7
]}

Coppola, Giovanni ^{[7
]}

Sloan, Steven A. ^{[8
]}

Hsieh, Christine L. ^{[9
,10
]}

Kim, Charles C. ^{[11
,23
]}

Bigio, Eileen H. ^{[12
]}

Weintraub, Sandra ^{[12
]}

Mesulam, Marek-Marsel ^{[12
]}

Rademakers, Rosa ^{[13
]}

Mackenzie, Ian R. ^{[14
,15
]}

Seeley, William W. ^{[3
,16
]}

Karydas, Anna ^{[3
,16
]}

Miller, Bruce L. ^{[3
,16
]}

Borroni, Barbara ^{[17
]}

Ghidoni, Roberta ^{[18
]}

Farese, Robert V., Jr. ^{[19
]}

Paz, Jeanne T. ^{[2
,3
]}

Barres, Ben A. ^{[8
]}

Huang, Eric J. ^{[1
,20
]}

机构：

[1] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA

[6] FORUM Pharmaceut, Waltham, MA 02451 USA

[7] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA

[8] Stanford Univ, Sch Med, Dept Neurobiol, Stanford, CA 94305 USA

[9] Univ Calif San Francisco, Immunol Sect, San Francisco VA Med Ctr, San Francisco, CA 94121 USA

[10] Univ Calif San Francisco, Dept Med, San Francisco, CA 94121 USA

[11] Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA

[12] Northwestern Univ, Feinberg Sch Med, Northwestern Alzheimer Dis Ctr, Chicago, IL 60611 USA

[13] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[14] Univ British Columbia, Dept Pathol, Vancouver, BC V5Z 1M9, Canada

[15] Vancouver Gen Hosp, Vancouver, BC V5Z 1M9, Canada

[16] Univ Calif San Francisco, Memory & Aging Ctr, San Francisco, CA 94158 USA

[17] Univ Brescia, Neurol Unit, Ctr Ageing Brain & Neurodegenerat Disorders, I-25100 Brescia, Italy

[18] IRCCS Ist Ctr San Giovanni Dio, Mol Markers Lab, I-25100 Brescia, Italy

[19] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, 665 Huntington Ave, Boston, MA 02115 USA

[20] San Francisco VA Med Ctr, Pathol Serv 113B, San Francisco, CA 94121 USA

[21] UC Berkeley UCSF Joint Med Program JMP, Sch Publ Hlth, Berkeley, CA 94720 USA

[22] Natl Taiwan Univ Hosp, Dept Pathol, Taipei 10002, Taiwan

[23] Verily, Mountain View, CA 94043 USA

来源：

CELL | 2016年 / 165卷 / 04期

关键词：

FRONTOTEMPORAL LOBAR DEGENERATION; NEURONAL CEROID-LIPOFUSCINOSIS; OBSESSIVE-COMPULSIVE DISORDER; NETWORK ANALYSIS; DEMENTIA; MUTATION; CELLS; C1Q; TRANSCRIPTOME; ORGANIZATION;

D O I：

10.1016/j.cell.2016.04.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：921 / 935

页数：15

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