CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

Pridans, Clare; Sauter, Kristin A.; Baer, Kristin; Kissel, Holger; Hume, David

doi:10.1038/srep03013

Cited by 61 publications

(72 citation statements)

References 35 publications

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“…We suggest that these vascular changes could have altered cerebral blood flow autoregulation resulting in regional ischemia similar to the mechanism proposed for the pathogenesis of leukoaraiosis (23). Therefore, it is possible that CSF1R mutation could set a limit to the degree of microglial proliferation (27), thus setting off events that culminate in the pathologic changes observed in the white matter. Therefore, it is possible that CSF1R mutation could set a limit to the degree of microglial proliferation (27), thus setting off events that culminate in the pathologic changes observed in the white matter.…”

Section: Discussionmentioning

confidence: 56%

Pathologic Staging of White Matter Lesions in Adult-Onset Leukoencephalopathy/Leukodystrophy With Axonal Spheroids

Alturkustani

Keith

Hazrati³

et al. 2015

J Neuropathol Exp Neurol

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The pathologic features of adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids (ALAS) are variable, and this has led to different hypotheses as to whether primarily demyelination or axonopathy may underlie this disorder. Typical ALAS pathology is rarely accompanied by focal multiple sclerosis (MS)-like plaques. In ALAS pathology accompanied by focal multiple sclerosis (MS)-like plaques cases, the pathologic features cannot be distinguished from those of progressive MS with diffusely abnormal white matter. To clarify these issues, we examined neuropathologic features in 159 representative samples from 5 ALAS cases (3 men and 2 women aged 39-61 years) and in 95 representative samples from 3 chronic MS cases (1 man and 2 women aged 50-73 years). The white matter abnormalities in ALAS cases were characterized by 3 evolving stages: 1) white matter with numerous spheroids in a background of well-myelinated fibers; 2) moderate loss of myelinated fibers with sparse to moderate number of spheroids; and 3) leukodystrophy-like pattern of confluent axonal and myelin loss. The application of this staging system suggests that myelin loss in ALAS is preceded by axonopathy. In progressive MS cases, the diffusely abnormal white matter pathology could be attributed to both primary demyelination and axonopathy. Some cases with predominant axonopathy are difficult to distinguish from cases with ALAS.

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Section: Discussionmentioning

confidence: 56%

Pathologic Staging of White Matter Lesions in Adult-Onset Leukoencephalopathy/Leukodystrophy With Axonal Spheroids

Alturkustani

Keith

Hazrati³

et al. 2015

J Neuropathol Exp Neurol

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“…One critical factor in microglial development and survival is CSFR1. Mice devoid of this receptor do not have microglia (8,20), and mutations that affect the function of the kinase domain of the receptor cause severe neurological syndromes in mice and humans (21)(22)(23)(24). In line with this, in 2014, Elmore et al showed that a chemical inhibitor of CSF1R virtually ablated the microglial population in the healthy brain.…”

Section: Lesson 3 As Long As the Blood-brain Barrier Is Intact Micrmentioning

confidence: 98%

Microglial Corpse Clearance: Lessons From Macrophages

et al. 2020

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From development to aging and disease, the brain parenchyma is under the constant threat of debris accumulation, in the form of dead cells and protein aggregates. To prevent garbage buildup, the brain is equipped with efficient phagocytes: the microglia. Microglia are similar, but not identical to other tissue macrophages, and in this review, we will first summarize the differences in the origin, lineage and population maintenance of microglia and macrophages. Then, we will discuss several principles that govern macrophage phagocytosis of apoptotic cells (efferocytosis), including the existence of redundant recognition mechanisms ("find-me" and "eat-me") that lead to a tight coupling between apoptosis and phagocytosis. We will then describe that resulting from engulfment and degradation of apoptotic cargo, phagocytes undergo an epigenetic, transcriptional and metabolic rewiring that leads to trained immunity, and discuss its relevance for microglia and brain function. In summary, we will show that neuroimmunologists can learn many lessons from the well-developed field of macrophage phagocytosis biology.

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“…Ligand-stimulated CSF-1R kinase activity was abolished for homodimeric receptors bearing each of 15 different missense mutations or each of four aberrant splice variants so far tested [40,41,47,50,51]. However, cotransfection experiments indicate that expression of the mutant chain does not suppress phosphorylation of the wild-type chain [47].…”

Section: Csf1r Mutations Cause Adult-onset Leukoencephalopathy With Amentioning

confidence: 99%

Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

Chiţu

Gökhan

Nandi

et al. 2016

Trends in Neurosciences

279

227

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The colony stimulating factor-1 receptor (CSF-1R) kinase regulates tissue macrophage homeostasis, osteoclastogenesis, and Paneth cell development. However, recent studies in mice have revealed that CSF-1R signaling directly controls the development and maintenance of microglia, and cell autonomously regulates neuronal differentiation and survival. While the CSF-1R-cognate ligands, CSF-1 and interleukin-34 (IL-34), compete for binding to the CSF-1R, they are expressed in a largely non-overlapping manner by mature neurons. The recent identification of a dominantly inherited, adult-onset, progressive dementia associated with inactivating mutations in the CSF-1R highlights the importance of CSF-1R signaling in the brain. We review the roles of the CSF-1R and its ligands in microglial and neural development and function, and their relevance to our understanding of neurodegenerative disease.

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CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

Cited by 61 publications

References 35 publications

Pathologic Staging of White Matter Lesions in Adult-Onset Leukoencephalopathy/Leukodystrophy With Axonal Spheroids

Pathologic Staging of White Matter Lesions in Adult-Onset Leukoencephalopathy/Leukodystrophy With Axonal Spheroids

Microglial Corpse Clearance: Lessons From Macrophages

Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

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