Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice
Open accessAbstract
Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein–43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.
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Mutations leading to haplo-insufficiency of GRN produce FTD syndromes characterized by TDP-43 pathology.
“Furthermore, mutations leading to haplo-insufficiency of GRN, a growth factor that has peripheral immune and central microglial regulatory functions (Petkau et al., 2010; Yin et al., 2010; Pickford et al., 2011), produce FTD syndromes characterized by TDP-43 pathology.”
From Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum (2020) · cites this paper as Yin et al., 2010
PGRN is expressed in microglia and neurons and shows higher expression once microglia respond to changes in their CNS environment.
“PGRN is expressed in microglia and neurons and shows higher expression once microglia respond to the changes in their CNS environment.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [339]
Grn loss of function causes microglial activation, cytosolic phosphorylated TDP-43 aggregation, myelin debris accumulation in white matter, and spatial learning and memory impairment in Grn-/- mice.
“Grn loss of function causes microglial activation,339,340 cytosolic phosphorylated TDP-43 aggregation,339,340 myelin debris accumulation in white matter, and spatial learning and memory impairment in Grn -/- mice.340”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [339]
In C9orf72 and GRN cases, dipeptide repeats or progranulin haploinsufficiency might set off neuroinflammation prior to the formation of large TDP-43 aggregates.
“while in C9orf72 and GRN cases, neuroinflammation could be triggered by dipeptide repeats or progranulin haploinsufficiency in advance of the large TDP-43 aggregates[14,17].”
From In vivo PET imaging of neuroinflammation in familial frontotemporal dementia (2021) · cites this paper as [17]
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- Authors
- Yin, F., Banerjee, R., Thomas, B., Zhou, P., Qian, L., Jia, T., Ma, X., Ma, Y., Iadecola, C., Beal, M. F., Nathan, C., & Ding, A.
- Affiliations
- Cornell University (US)
- Weill Cornell Medicine (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Ding, Aihao
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2009-12-21
- Volume
- 207
- Issue
- 1
- Pages
- 117-128
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2812536
- OpenAlex
- W2140447941
- Cited by
- 480
- References
- 33
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 32 · 2023: 34 · 2022: 23 · 2021: 32 · 2020: 30 · 2019: 34 · 2018: 37 · 2017: 35 · 2016: 31 · 2015: 27 · 2014: 19 · 2013: 28 · 2012: 26
- FWCI
- 16.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM061710, GM061710)
- National Institute of Allergy and Infectious Diseases (R01AI030165)
- National Institute of Neurological Disorders and Stroke (R01NS034179, R01NS060885, NS060885, R01NS035806, NS34179, NS-35806, R37NS034179)
- 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, neuroinflammation, microglia, macrophages, Listeria monocytogenes infection, host defense, hippocampal neurons, oxygen-glucose deprivation, tau phosphorylation, astrocyte activation, IL-10, inflammatory cytokines, neurodegeneration
- MeSH terms
- Progranulins, Granulins, Aging, Animals, Astrocytes, Brain Ischemia, Hippocampus, Humans, Inflammation, Listeriosis, Listeria monocytogenes, Macrophages, Interleukin-10, Microglia, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Mice, Frontotemporal Dementia
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