Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation
Open accessAbstract
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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Dysregulation of microglial phagocytosis of synapses has been implicated in the pathology of diverse neurological diseases.
“Dysregulation of microglial phagocytosis of synapses has been implicated in the pathology of diverse neurological diseases (Hong et al., 2016; Lui et al., 2016; Vasek et al., 2016), failure to clear myelin debris contributes to CNS regenerative failure (Vargas and Barres, 2007), and problems with microglial uptake and clearance may contribute to aging-associated cognitive decline (Safaiyan et al.,”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Lui et al., 2016
Housekeeping functions include synaptic remodeling, migration to sites of neuronal death for phagocytosis, and maintenance of myelin homeostasis.
“Physiological housekeeping functions include synaptic remodeling (a function critical for CNS development, homeostasis, and neurodegeneration20–22), migration to sites of neuronal death to phagocytose dead or dying cells23,24 or debris, and maintaining myelin homeostasis25.”
From Microglia in neurodegeneration (2018) · cites this paper as [21]
Progranulin deficiency causes age-dependent, progressive upregulation of lysosomal and innate immunity genes, more complement production, and enhanced C1q-dependent synaptic pruning by microglia.
“Progranulin deficiency leads to age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced C1q-dependent synaptic pruning by microglia”
From Microglia in neurodegeneration (2018) · cites this paper as [21]
Grn loss of function profoundly impacts microglial state and function, which plays a critical role in FTD pathogenesis.
“In the CNS, Grn loss of function profoundly impacts the microglial state and function, which plays a critical role in FTD pathogenesis.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [348]
Grn deficiency causes synaptic loss by microglia-mediated synaptic pruning via complement; deletion of C1qa significantly reduced synaptic pruning by Grn-/- microglia and ameliorated behavioral deficits, neuronal cell loss, and increased survival in Grn-/- mice.
“Deficiency of Grn caused synaptic loss by microglia-mediated synaptic pruning via complement involvement as deletion of the C1qa gene (which encodes complement C1q subcomponent subunit A) significantly reduced synaptic pruning by Grn-/-microglia, and ameliorated behavioral deficits, neuronal cell loss and increased survival in Grn-/- mice.348”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [348]
Synaptic dysfunction and loss might be one of the earliest pathological mechanisms in the course of neurodegeneration.
“Synaptic dysfunction and loss might be one of the earliest pathological mechanisms in the course of neurodegeneration (Gong and Lippa 2010; Janezic et al. 2013; Lui et al. 2016; Marttinen et al. 2015; Masliah et al. 2001; Selkoe 2002).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Lui et al. 2016
iMGLs can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB.
“In addition to AD GWAS genes, iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS and therefore, can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB in which microglia may play a prominent role (Bachstetter et al., 2015; Crotti et al., 2014; Lui et al., 2016; O’Rourke et al., 2016)(Figure S6C).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Lui et al., 2016
iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS.
“In addition to AD GWAS genes, iMGLs express other CNS disease-related genes including APP, PSEN1/2, HTT, GRN, TARDBP, LRRK2, C9orf72, SOD1, VCP, and FUS and therefore, can likely be used to study other neurological diseases such as ALS, HD, FTD, and DLB in which microglia may play a prominent role (Bachstetter et al., 2015; Crotti et al., 2014; Lui et al., 2016; O’Rourke et al., 2016)(Figure S6C).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Lui et al., 2016
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- Authors
- 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., Seeley, W. W., Karydas, A., Miller, B. L., Borroni, B., Ghidoni, R., Farese, R. V., Paz, J. T., Barres, B. A., & Huang, E. J.
- Affiliations
- University of California, San Francisco (US)
- FORUM Pharmaceuticals (United States) (US)
- University of California, Los Angeles (US)
- Stanford Medicine (US)
- San Francisco VA Medical Center (US)
- Northwestern University (US)
- Mayo Clinic (US)
- University of British Columbia (CA)
- University of Brescia (IT)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Harvard University (US)
- Corresponding author
- Huang, Eric J.
- ORCID
- Lui, Hansen
- Zhang, Jiasheng
- Cahill, Michelle K.
- Kelley, Kevin W.
- Huang, Hsin-Yi
- Oldham, Michael C.
- Gao, Fuying
- Coppola, Giovanni
- Sloan, Steven A.
- Hsieh, Christine L.
- Kim, Charles C.
- Bigio, Eileen H.
- Rademakers, Rosa
- Mackenzie, Ian R.
- Seeley, William W.
- Miller, Bruce L.
- Borroni, Barbara
- Ghidoni, Roberta
- Farese, Robert V.
- Paz, Jeanne T.
- Barres, Ben A.
- Huang, Eric J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 165
- Issue
- 4
- Pages
- 921-935
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4860138
- OpenAlex
- W2341088037
- Cited by
- 729
- References
- 44
- Citations by year
- 2026: 49 · 2025: 67 · 2024: 70 · 2023: 88 · 2022: 66 · 2021: 86 · 2020: 72 · 2019: 72 · 2018: 70 · 2017: 68 · 2016: 20
- FWCI
- 42.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002690, I01 BX001108, I01 RX002133, I01 BX002978)
- Ministero della Salute
- University of British Columbia
- National Institutes of Health (UL1TR001422)
- National Institute on Aging (P30AG013854, P01AG019724, P50AG023501)
- National Institute of General Medical Sciences (T32GM007618, T32GM008568)
- National Institute of Allergy and Infectious Diseases (P30AI027763)
- National Institute of Neurological Disorders and Stroke (R00NS078118, R01NS096369, P30NS062691)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- progranulin, frontotemporal dementia, microglial activation, synaptic pruning, complement activation, C1QA, neurodegeneration, aging, thalamocortical circuits, ventral thalamus, hyperexcitability, lysosomal genes, innate immunity
- MeSH terms
- Progranulins, Granulins, Aging, Animals, Brain, Cerebrospinal Fluid, Complement Activation, Humans, Immunity, Innate, Lysosomes, Obsessive-Compulsive Disorder, Synapses, Thalamus, Complement C1q, Microglia, Intercellular Signaling Peptides and Proteins, Mice, Metabolic Networks and Pathways, Frontotemporal Dementia
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