ArticleActa neuropathologica2023
Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination.
Article in Acta neuropathologica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 19 citations in OpenAlex.
- Progranulin deficiency perturbs lipid metabolism in white matter microglia.bioRxiv : the preprint server for biology · 2026Article
- Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.International journal of molecular sciences · 2026Review
- Regulation of microglial activation by progranulin through the NF-κB pathway in subarachnoid hemorrhage and its effect on white matter injury.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Selective neuronal restoration of progranulin does not prevent the frontotemporal dementia like-phenotype of progranulin knockout mice.Journal of neuroinflammation · 2026Article
- Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?Frontiers in aging neuroscience · 2026Review
- PGRN Counteracts the Associations of Abnormal Tau Proteins with Neurodegeneration and Cognitive Decline in Non-demented Adults: A Longitudinal Study.Molecular neurobiology · 2025Article
- Review
- The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- Activated TBK1 promotes ACSL1-mediated microglia lipid droplet accumulation and neuroinflammation in Parkinson's disease.Journal of neuroinflammation · 2025Article
- sPLA2-IIA modifies progranulin deficiency phenotypes in mouse models.Molecular neurodegeneration · 2025Article
- Progranulin deficiency in the brain: the interplay between neuronal and non-neuronal cells.Translational neurodegeneration · 2025Review
- White matter pathology in FTLD caused by GRN mutations.Acta neuropathologica · 2025Article
- Progranulin deficiency does not exacerbate TDP-43 pathology in TDP-43 transgenic mouse models.NPJ dementia · 2025Article
- Fundamental Neurochemistry Review: Lipids across microglial states.Journal of neurochemistry · 2025Review
- Recognizing Alzheimer's disease from perspective of oligodendrocytes: Phenomena or pathogenesis?CNS neuroscience & therapeutics · 2024Review
- Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease.Journal of neuroinflammation · 2023Review
- Regulation of extracellular progranulin in medial prefrontal cortex.Neurobiology of disease · 2023Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Heterozygous mutations in the granulin (GRN) gene, resulting in the haploinsufficiency of the progranulin (PGRN) protein, is a leading cause of frontotemporal lobar degeneration (FTLD). Complete loss of the PGRN protein causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Polymorphisms in the GRN gene have also been associated with several other neurodegenerative diseases, including Alzheimer's disease (AD), and Parkinson's disease (PD). PGRN deficiency has been shown to cause myelination defects previously, but how PGRN regulates myelination is unknown. Here, we report that PGRN deficiency leads to a sex-dependent myelination defect with male mice showing more severe demyelination in response to cuprizone treatment. This is accompanied by exacerbated microglial proliferation and activation in the male PGRN-deficient mice. Interestingly, both male and female PGRN-deficient mice show sustained microglial activation after cuprizone removal and a defect in remyelination. Specific ablation of PGRN in microglia results in similar sex-dependent phenotypes, confirming a microglial function of PGRN. Lipid droplets accumulate in microglia specifically in male PGRN-deficient mice. RNA-seq analysis and mitochondrial function assays reveal key differences in oxidative phosphorylation in male versus female microglia under PGRN deficiency. A significant decrease in myelination and accumulation of myelin debris and lipid droplets in microglia were found in the corpus callosum regions of FTLD patients with GRN mutations. Taken together, our data support that PGRN deficiency leads to sex-dependent alterations in microglia with subsequent myelination defects.
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