Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Wang, Yanli; Wang, Fang-Ze; Li, Runzhi; Jiang, Jiwei; Liu, Xiangrong; Xu, Jun

doi:10.3389/fnagi.2021.792840

Cited by 6 publications

(8 citation statements)

References 40 publications

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“… 24 CSF1R ‐related leukoencephalopathy is characterized by a predominant involvement of microglia, classifying as microgliopathy. 10 , 25 Approximately 95% of previously reported CSF1R variants linked to leukoencephalopathy are located within the TKD, leading to the impairment of autophosphorylation. In vitro experiments have shown that cells expressing mutant CSF1R fail to exhibit ligand‐induced autophosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a novel intronic splicing mutation in CSF1R‐related leukoencephalopathy

Han,

et al. 2024

CNS Neurosci Ther

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AimsColony stimulating factor 1 receptor (CSF1R)‐related leukoencephalopathy is a rapidly progressing neurodegenerative disease caused by CSF1R gene mutations. This study aimed to identify and investigate the effect of a novel intronic mutation (c.1754‐3C>G) of CSF1R on splicing.MethodsA novel intronic mutation was identified using whole‐exome sequencing. To investigate the impact of this mutation, we employed various bioinformatics tools to analyze the transcription of the CSF1R gene and the three‐dimensional structure of its encoded protein. Furthermore, reverse transcription polymerase chain reaction (RT‐PCR) was performed to validate the findings.ResultsA novel mutation (c.1754‐3C>G) in CSF1R was identified, which results in exon 13 skipping due to the disruption of the 3′ splice site consensus sequence NYAG/G. This exon skipping event was further validated in the peripheral blood of the mutation carrier through RT‐PCR and Sanger sequencing. Protein structure prediction indicated a disruption in the tyrosine kinase domain, with the truncated protein showing significant structural alterations.ConclusionsOur findings underscore the importance of intronic mis‐splicing mutations in the diagnosis and management of CSF1R‐related leukoencephalopathy.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of a novel intronic splicing mutation in CSF1R‐related leukoencephalopathy

Han,

et al. 2024

CNS Neurosci Ther

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“…Recent clinical reviews have focused on the diagnosis of adult leukodystrophies, and particularly on “microglial leukoencephalopathies” [ 198 , 199 , 200 ]. Hematopoietic stem cell transplantation has been used in a few clinical trials with variable results [ 110 , 199 , 201 , 202 , 203 , 204 ]. More specific attempts to treat CSF1R-microglial encephalopathy are focused on microglial-based therapies [ 205 ].…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, PLOSL has been considered a primary microgliopathy [ 1 , 7 ]. Since microglia and osteoclasts are affected in NHD, redefinition of the disease as a multisystemic “immunological” disease has also been proposed [ 110 ]. Treatments directed only to microglia will be inefficient to cover the complex pathology in NHD.…”

Section: Discussionmentioning

confidence: 99%

The Primary Microglial Leukodystrophies: A Review

Ferrer

2022

IJMS

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Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu–Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic “immunological” disease.

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“…More recently, CSF1 and its receptor CSFR1, showed significant upregulation in microglia surrounding the Abeta plaques and as such, has been proposed as a marker of neurodegenerative diseases [90]. Likewise, Csf1 mRNA is increased in CSF1R-microglialencephalopathy or glia-original dementia, a rare autosomal dominant disease caused by mutations in the gene coding for CSF1R resulting in microglial dysfunction [184]. Finally, Csf1 transcripts were found to be upregulated in the ischemic hemisphere of a mouse model of stroke [86].…”

Section: Brain Macrophages Responses To Strokementioning

confidence: 99%

Neuroglia Cells Transcriptomic in Brain Development, Aging and Neurodegenerative Diseases

Pinosanu¹,

Capitanescu²,

Glăvan³

et al. 2023

Aging and disease

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Glia cells are essential for brain functioning during development, aging and disease. However, the role of astroglia plays during brain development is quite different from the role played in the adult lesioned brain. Therefore, a deeper understanding of pathomechanisms underlying astroglia activity in the aging brain and cerebrovascular diseases is essential to guide the development of new therapeutic strategies. To this end, this review provides a comparison between the transcriptomic activity of astroglia cells during development, aging and neurodegenerative diseases, including cerebral ischemia. During fetal brain development, astrocytes and microglia often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, and synaptic pruning. In the adult brain astrocytes are a critical player in the synapse remodeling by mediating synapse elimination while microglia activity has been associated with changes in synaptic plasticity and remove cell debris by constantly sensing the environment. However, in the lesioned brain astrocytes proliferate and play essential functions with regard to energy supply to the neurons, neurotransmission and buildup of a protective scar isolating the lesion site from the surroundings. Inflammation, neurodegeneration, or loss of brain homeostasis induce changes in microglia gene expression, morphology, and function, generally referred to as "primed" microglia. These changes in gene expression are characterized by an enrichment of phagosome, lysosome, and antigen presentation signaling pathways and is associated with an up-regulation of genes encoding cell surface receptors. In addition, primed microglia are characterized by upregulation of a network of genes in response to interferon gamma. Conclusion. A comparison of astroglia cells transcriptomic activity during brain development, aging and neurodegenerative disorders might provide us with new therapeutic strategies with which to protect the aging brain and improve clinical outcome.

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Recent Advances in Basic Research for CSF1R-Microglial Encephalopathy

Cited by 6 publications

References 40 publications

Identification and characterization of a novel intronic splicing mutation in CSF1R‐related leukoencephalopathy

Identification and characterization of a novel intronic splicing mutation in CSF1R‐related leukoencephalopathy

The Primary Microglial Leukodystrophies: A Review

Neuroglia Cells Transcriptomic in Brain Development, Aging and Neurodegenerative Diseases

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