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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; 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.
Afiliação
  • Lui H; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Zhang J; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Makinson SR; Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Cahill MK; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Kelley KW; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Huang HY; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Shang Y; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Oldham MC; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Martens LH; FORUM Pharmaceuticals, Waltham, MA 02451, USA.
  • Gao F; Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Coppola G; Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Sloan SA; Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Hsieh CL; Immunology Section, San Francisco VA Medical Center and Department of Medicine, University of California, San Francisco, San Francisco, CA 94121, USA.
  • Kim CC; Department of Medicine, University of California, San Francisco, San Francisco, CA 94110, USA.
  • Bigio EH; Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • Weintraub S; Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • Mesulam MM; Northwestern Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • Rademakers R; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Mackenzie IR; Department of Pathology, University of British Columbia and Vancouver General Hospital, Vancouver, BC V5Z 1M9, Canada.
  • Seeley WW; Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Karydas A; Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Miller BL; Department of Neurology and Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Borroni B; Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia 25100, Italy.
  • Ghidoni R; Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia 25100, Italy.
  • Farese RV; Department of Genetics and Complex Diseases, School of Public Health, Harvard University, Boston, MA 02115, USA.
  • Paz JT; Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Barres BA; Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Huang EJ; 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.
Cell ; 165(4): 921-35, 2016 May 05.
Article em En | MEDLINE | ID: mdl-27114033
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / Envelhecimento / Complemento C1q / Microglia / Ativação do Complemento / Peptídeos e Proteínas de Sinalização Intercelular Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / Envelhecimento / Complemento C1q / Microglia / Ativação do Complemento / Peptídeos e Proteínas de Sinalização Intercelular Limite: Animals / Humans Idioma: En Revista: Cell Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos