Colony stimulating factors in the nervous system

Chiţu, Violeta; Biundo, Fabrizio; Stanley, E. Richard

doi:10.1016/j.smim.2021.101511

Cited by 29 publications

(36 citation statements)

References 434 publications

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“…The CSF1R is a protein tyrosine kinase receptor that consists of five immunoglobulin-like domains in the extracellular ligand-binding portion, a single transmembrane domain, a juxtamembrane domain, a kinase insertion domain, and two intracellular TKDs ( Tarale and Alam, 2022 ). Approximately 95% of CSF1R gene mutations are located in the TKD of CSF1R encoded by exons 12–21, especially exons 18 and 19 ( Leng et al, 2019 ; Zhuang et al, 2020 ; Chitu et al, 2021 ). No disease-associated mutations have been discovered yet in exon 16 ( Tian et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…We speculated that the identified variant might be subject to genetic modifiers that prevent its manifestation. The possibility that these unaffected individuals may develop symptoms at an older age cannot be disregarded, considering that the age of onset has been noted even at 78 years ( Chitu et al, 2021 ). It is noteworthy that although only a few non-specific white matter lesions were observed on structural brain MRI in patient III-11, pCASL demonstrated a marked decrease in the CBF in the bilateral periventricular areas, corona radiata, and corpus callosum that was not captured by the structural brain MRI.…”

Section: Discussionmentioning

confidence: 99%

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Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease.Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation.Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members.Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Jiang

Wang

et al. 2022

Front. Cell Dev. Biol.

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“…Subsequent studies in autopsied brain tissue of CRL patients showed increased expression of CSF2 (10) and provided evidence of dysregulated G-CSF signaling (6, 7) suggesting an important role for these factors in CRL. Since the CSF-1R, as well as the receptors for both G- and GM-CSF, are predominantly expressed in microglia and regulate their activation (reviewed in (11)), it was suggested that CRL could be a primary microgliopathy. Indeed, monoallelic deletion of Csf1r in the microglial lineage recapitulated the phenotype observed in Csf1r +/- mice, indicating that CRL is a primary microgliopathy (8).…”

Section: Discussionmentioning

confidence: 99%

“…Elevation of CSF2 expression in CRL patient brains (10) and the identification of gene expression changes consistent with altered G-CSF signaling (6, 7) suggested that both GM-CSF and G-CSF may also contribute to the development of this disease. Notably, while the expression of transcripts for both growth factors is barely detectable in normal brains, they can be rapidly induced by a variety of inflammatory stimuli, tissue injury and neurotoxins and signal in microglia to promote functional changes (reviewed in (11)). GM-CSF is a microglial mitogen (12, 13) that promotes a demyelinating phenotype in microglia (14), while G-CSF induces a pro- oxidant phenotype (15).…”

Section: Introductionmentioning

confidence: 99%

Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy

Biundo

Chiţu

Tindi

et al. 2022

Preprint

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Colony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r+/- mouse. The expression of Csf2, encoding granulocyte- macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of mouse CRL, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In this manuscript, we investigate the behavioral, electrophysiological and histopathological phenotypes of CRL mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r+/- mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not their cognitive impairment. Consistent with this, Csf3 heterozygosity attenuated microglial activation in the cerebellum and in the ventral but not in the dorsal hippocampus. Csf3 heterozygosity also failed to prevent demyelination. Csf1r+/- mice exhibited altered synaptic activity in the deep cerebellar nuclei (DCN) associated with increased deposition of the complement factor C1q on glutamatergic synapses and with increased engulfment of glutamatergic synapses by DCN microglia. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3. Our findings indicate that G-CSF and GM-CSF play non-overlapping roles in mouse CRL development and suggest that G-CSF could be an additional therapeutic target in CRL.

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“…Removal of the IL-33 receptor specifically in microglia reduces newborn neuron integration, causing impaired memory precision [ 82 ]. IL-34 secreted by neurons binds to CSF-1R on microglia to enhance their proliferation, survival, and function [ 83 ]. ATP local release by activated neurons mediates microglial process motility via binding to microglial P2Y12 receptor.…”

Section: Origin and Physiological Function Of Microgliamentioning

confidence: 99%

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

Deng

et al. 2022

Biomolecules

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Alzheimer’s disease (AD) is the most common progressive and irreversible neurodegeneration characterized by the impairment of memory and cognition. Despite years of studies, no effective treatment and prevention strategies are available yet. Identifying new AD therapeutic targets is crucial for better elucidating the pathogenesis and establishing a valid treatment of AD. Growing evidence suggests that microglia play a critical role in AD. Microglia are resident macrophages in the central nervous system (CNS), and their core properties supporting main biological functions include surveillance, phagocytosis, and the release of soluble factors. Activated microglia not only directly mediate the central immune response, but also participate in the pathological changes of AD, including amyloid-beta (Aβ) aggregation, tau protein phosphorylation, synaptic dissection, neuron loss, memory function decline, etc. Based on these recent findings, we provide a new framework to summarize the role of microglia in AD memory impairment. This evidence suggests that microglia have the potential to become new targets for AD therapy.

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Colony stimulating factors in the nervous system

Cited by 29 publications

References 434 publications

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Granulocyte Colony Stimulating Factor causes cerebellar deficits and anxiety in a mouse model of CSF-1 receptor-related leukoencephalopathy

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

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