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.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
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.
UR - https://www.scopus.com/pages/publications/84963969178
U2 - 10.1016/j.cell.2016.04.001
DO - 10.1016/j.cell.2016.04.001
M3 - Article
C2 - 27114033
AN - SCOPUS:84963969178
SN - 0092-8674
VL - 165
SP - 921
EP - 935
JO - Cell
JF - Cell
IS - 4
ER -