Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Kondo, Yoichi; Adams, Jeffrey; Vanier, Marie T.; Duncan, Ian D.

doi:10.1523/jneurosci.6344-10.2011

Cited by 53 publications

(57 citation statements)

References 72 publications

(84 reference statements)

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“…In agreement with that finding, we observed CSF1R is a cell surface receptor for the cytokine CSF1, which regulates the survival, proliferation, differentiation, and function of mononuclear phagocytic cells, including microglia and macrophages of the CNS (17). Moreover, several functions of CSF1R signaling that contribute to the white matter development, remyelination, or neuronal maturation have been reported (8,18,19); it is unknown which of these functions may be affected most in the pathogenesis of HDLS. Perturbation of CSF1R signaling by haploinsufficiency has recently been reported in HDLS patients (8).…”

Section: Discussionsupporting

confidence: 89%

Early Pathologic Changes in Hereditary Diffuse Leukoencephalopathy With Spheroids

Riku

Ando

Goto

et al. 2014

J Neuropathol Exp Neurol

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Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a familial neurodegenerative disease clinically characterized by progressive cognitive and motor dysfunction. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene have recently been identified in HDLS patients. The presence of diffuse axonal spheroids, myelin loss, and pigmented microglia in the white matter are pathologic hallmarks of HDLS; however, early pathologic findings have not been described in HDLS patients. We report a Japanese family with HDLS. A novel heterozygous c.653 C>Y mutation in the CSF1R gene was identified in the female proband who died at the age of 63 years; postmortem findings were compatible with HDLS. We also autopsied her sister who was considered to be neurologically asymptomatic and died of tuberculosis at the age of 44 years. Postmortem studies revealed patchy axonal degeneration and myelin loss, predominantly in the subcortical white matter. Pigmented microglia were distributed diffusely throughout the cerebral white matter and expressed CSF1R poorly. In conclusion, our observations suggest that the pathology of HDLS may initially be characterized by multifocal lesions in subcortical white matter regions. Moreover, pigmented microglia poorly express CSF1R and are distributed diffusely throughout the white matter at the early disease stage, preceding axonal damage and myelin loss.

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Section: Discussionsupporting

confidence: 89%

Early Pathologic Changes in Hereditary Diffuse Leukoencephalopathy With Spheroids

Riku

Ando

Goto

et al. 2014

J Neuropathol Exp Neurol

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“…The cellular source of TnC remains an open but important question related to GLD pathology. We speculate that if TnC is not transcriptionally regulated by psychosine then inflammatory factors, such as TNF and/or interleukin-1 (IL-1) (41, 42), which are greatly upregulated in GLD brains (43), may modify the ECM in GLD.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the presence of TnC may stimulate microglia to express more TnC receptors, from which downstream signaling may result in functionally different outcomes. Microglia express αv and β1 integrins (45), and while altered integrin expression on microglia may result from psychosine levels in GLD, other cytokines that are also produced in the CNS during GLD may also contribute to microglial activation (43). In particular, the cytokines transforming growth factor β, TNF, and IL-1β, which are known to be elevated in GLD, have also been reported to induce a diversity of α and β integrin expression on microglia (45).…”

Section: Discussionmentioning

confidence: 99%

Aberrant Production of Tenascin-C in Globoid Cell Leukodystrophy Alters Psychosine-Induced Microglial Functions

Claycomb

Winokur

Johnson

et al. 2014

J Neuropathol Exp Neurol

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Globoid cell leukodystrophy (GLD), or Krabbe disease, is a rare and often fatal demyelinating disease caused by mutations in the galactocerebrosidase (galc) gene that result in accumulation of galactosylsphingosine (‘psychosine’). We recently reported that the extracellular matrix (ECM) protease, matrix metalloproteinase (MMP)-3, is elevated in GLD and that it regulates psychosine-induced microglial activation. Here, we examined central nervous system ECM component expression in human GLD patients and in the twitcher mouse model of GLD using immunohistochemistry. The influence of ECM proteins on primary murine microglial responses to psychosine was evaluated using ECM proteins as substrates and analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), immunocytochemistry, and ELISA. Functional analysis of microglial cytotoxicity was performed on oligodendrocytes in co-culture and cell death was measured by lactose dehydrogenase assay. Tenascin-C (TnC) was expressed at higher levels in human GLD and in twitcher mice vs. controls. Microglial responses to psychosine were enhanced by TnC, as determined by an increase in ‘globoid-like’ cell formation, MMP-3 mRNA expression and higher toxicity toward oligodendrocytes in culture. These findings were consistent with a shift toward the M1 microglial phenotype in TnC grown microglia. Thus, elevated TnC expression in GLD modified microglial responses to psychosine. These data offer a novel perspective and enhance understanding of the microglial contribution to GLD pathogenesis.

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“…They do not survive beyond 45 days. However, an extended lifespan has been reported when its genetic background is altered [67,68]. The neuropathology is characterized by the infiltration of periodic acid schiff (PAS)-positive macrophages (so-called globoid cells) concomitant or prior to demyelination both in the white matter of CNS and PNS.…”

Section: The Twitcher Mousementioning

confidence: 99%

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

2011

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The leukodystrophies are rare and serious genetic disorders of the central nervous system that primarily affect children who frequently die early in life or have significantly delayed motor and mental milestones that result in long-term disability. Although with some of these disorders, early intervention with bone marrow or cord blood transplantation has been proven useful, it has not yet been determined that such therapies promote myelin repair of the central nervous system. Research on experimental therapies aimed at myelin repair is aided by the ability to test cell replacement strategies in genetic models in which the mutations and neuropathology match the human disorder. Thus, models exist of Pelizaeus-Merzbacher disease and the lysosomal storage disorder, Krabbe disease, which reflect the clinical and pathological course of the human disorders. Collectively, animals with mutations in myelin genes are called the myelin mutants, and they include rodent models such as the shiverer mouse that have been extensively used to study myelination by exogenous cell transplantation. These studies have encompassed many permutations of the age of the recipient, type of transplanted cell, site of engraftment, and so forth, and they offer hope that the scaling up of myelin produced by transplanted cells will have clinical significance in treating patients. Here we review these models and discuss their relative importance and use in such translational approaches. We discuss how grafts are identified and functional outcomes are measured. Finally, we briefly discuss the cells that have been successfully transplanted, which may be used in future clinical trials.

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Macrophages Counteract Demyelination in a Mouse Model of Globoid Cell Leukodystrophy

Cited by 53 publications

References 72 publications

Early Pathologic Changes in Hereditary Diffuse Leukoencephalopathy With Spheroids

Early Pathologic Changes in Hereditary Diffuse Leukoencephalopathy With Spheroids

Aberrant Production of Tenascin-C in Globoid Cell Leukodystrophy Alters Psychosine-Induced Microglial Functions

The Myelin Mutants as Models to Study Myelin Repair in the Leukodystrophies

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