Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
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.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Hansen
H
Lui
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Jiasheng
J
Zhang
Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Stefanie R
SR
Makinson
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Michelle K
MK
Cahill
Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Kevin W
KW
Kelley
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Hsin-Yi
HY
Huang
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Yulei
Y
Shang
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
Michael C
MC
Oldham
FORUM Pharmaceuticals, Waltham, MA 02451, USA.
Lauren Herl
LH
Martens
Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Fuying
F
Gao
Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Giovanni
G
Coppola
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Steven A
SA
Sloan
Immunology Section, San Francisco VA Medical Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94121, USA.
Christine L
CL
Hsieh
Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
Charles C
CC
Kim
Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Eileen H
EH
Bigio
Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Sandra
S
Weintraub
Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Marek-Marsel
MM
Mesulam
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Rosa
R
Rademakers
Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada.
Ian R
IR
Mackenzie
Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
William W
WW
Seeley
Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Anna
A
Karydas
Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
Bruce L
BL
Miller
Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia 25100, Italy.
Barbara
B
Borroni
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia 25100, Italy.
Roberta
R
Ghidoni
Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, MA 02115, USA.
Robert V
RV
Farese
Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Jeanne T
JT
Paz
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ben A
BA
Barres
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.
Eric J
EJ
Huang
D000375:Aging / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002555:Cerebrospinal Fluid; D003167:Complement Activation; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism*; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism; D000077155:Granulins; D006801:Humans; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009771:Obsessive-Compulsive Disorder / Q000235:genetics / Q000378:metabolism; D000077153:Progranulins; D013569:Synapses / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism
D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D015922:Complement C1q