Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

O’Sullivan, Catherine; Dev, Kumlesh K.

doi:10.1242/jcs.169342

Cited by 40 publications

(72 citation statements)

References 51 publications

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“…Exposure to Yoda‐1 or psychosine caused similar levels of demyelination (Figure g). We have previously reported that psychosine induces demyelination of organotypic cerebellar slices (Misslin et al, ; O'Sullivan & Dev, ) and have used this system as an ex vivo model of the dysmyelination that occurs in Krabbe disease (Giri et al, ). Importantly, blocking Piezo1 channels with GsMTx4 prevented psychosine‐mediated demyelination.…”

Section: Resultsmentioning

confidence: 99%

“…Galactosylsphingosine or psychosine (Santa Cruz Biotechnology, sc-202781) is a cationic lysosphingolipid that accumulates in the brains of patients with Krabbe disease (Giri et al, 2002) and causes oligodendrocyte cell death and demyelination (Misslin, Velasco-Estevez, Albert, O'Sullivan, & Dev, 2017;O'Sullivan & Dev, 2015).…”

Section: Reagentsmentioning

confidence: 99%

“…* represents a statistically significant difference (p < .05) from control and # represents a statistically significant difference (p < .05) between psychosine and PSY + GsMTx4 groups [Color figure can be viewed at wileyonlinelibrary.com] demyelination (Figure 2g). We have previously reported that psychosine induces demyelination of organotypic cerebellar slices (Misslin et al, 2017;O'Sullivan & Dev, 2015) and have used this system as an ex vivo model of the dysmyelination that occurs in Krabbe disease (Giri et al, 2002). Importantly, blocking Piezo1 channels with GsMTx4 prevented psychosine-mediated demyelination.…”

Section: Blocking Mechanosensitive Ion Channels Enhances Myelinatiomentioning

confidence: 99%

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Inhibition of Piezo1 attenuates demyelination in the central nervous system

Velasco‐Estevez

Gadalla

Liñan-Barba

et al. 2019

Glia

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Piezo1 is a mechanosensitive ion channel that facilitates the translation of extracellular mechanical cues to intracellular molecular signaling cascades through a process termed, mechanotransduction. In the central nervous system (CNS), mechanically gated ion channels are important regulators of neurodevelopmental processes such as axon guidance, neural stem cell differentiation, and myelination of axons by oligodendrocytes. Here, we present evidence that pharmacologically mediated overactivation of Piezo1 channels negatively regulates CNS myelination. Moreover, we found that the peptide GsMTx4, an antagonist of mechanosensitive cation channels such as Piezo1, is neuroprotective and prevents chemically induced demyelination. In contrast, the positive modulator of Piezo1 channel opening, Yoda‐1, induces demyelination and neuronal damage. Using an ex vivo murine‐derived organotypic cerebellar slice culture model, we demonstrate that GsMTx4 attenuates demyelination induced by the cytotoxic lipid, psychosine. Importantly, we confirmed the potential therapeutic effects of GsMTx4 peptide in vivo by co‐administering it with lysophosphatidylcholine (LPC), via stereotactic injection, into the cerebral cortex of adult mice. GsMTx4 prevented both demyelination and neuronal damage usually caused by the intracortical injection of LPC in vivo; a well‐characterized model of focal demyelination. GsMTx4 also attenuated both LPC‐induced astrocyte toxicity and microglial reactivity within the lesion core. Overall, our data suggest that pharmacological activation of Piezo1 channels induces demyelination and that inhibition of mechanosensitive channels, using GsMTx4, may alleviate the secondary progressive neurodegeneration often present in the latter stages of demyelinating diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Reagentsmentioning

confidence: 99%

Section: Blocking Mechanosensitive Ion Channels Enhances Myelinatiomentioning

confidence: 99%

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Inhibition of Piezo1 attenuates demyelination in the central nervous system

Velasco‐Estevez

Gadalla

Liñan-Barba

et al. 2019

Glia

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“…9063 and 11065), as per the ethics outlined by the supplier and as we have described previously [41, 46–48]. Human astrocytes were cultured at 37 °C and 5 % CO 2 in a humidified incubator and grown in human astrocyte speciality media (ScienCell; 1801) or standard DMEM/F12 media (Fisher; 10770245) supplemented with 1 % astrocyte growth supplement (ScienCell; 1852), 10 % fetal bovine serum (FBS, Sigma; F7524) and 1 % penicillin/streptomycin (pen/strep, Sigma; P4333) in T75 culture flasks (Corning) unless otherwise indicated in the figure legends.…”

Section: Methodsmentioning

confidence: 99%

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

O’Sullivan

Gasparini

Mir

et al. 2016

J Neuroinflammation

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BackgroundThe fractalkine (CX3CR1) ligand is expressed in astrocytes and reported to be neuroprotective. When cleaved from the membrane, soluble fractalkine (sCX3CL1) activates the receptor CX3CR1. Although somewhat controversial, CX3CR1 is reported to be expressed in neurons and microglia. The membrane-bound form of CX3CL1 additionally acts as an adhesion molecule for microglia and infiltrating white blood cells. Much research has been done on the role of fractalkine in neuronal cells; however, little is known about the regulation of the CX3CL1 ligand in astrocytes.MethodsThe mechanisms involved in the up-regulation and cleavage of CX3CL1 from human astrocytes were investigated using immunocytochemistry, Q-PCR and ELISA. All statistical analysis was performed using GraphPad Prism 5.ResultsA combination of ADAM17 (TACE) and ADAM10 protease inhibitors was found to attenuate IL-1β-, TNF-α- and IFN-γ-induced sCX3CL1 levels in astrocytes. A specific ADAM10 (but not ADAM17) inhibitor also attenuated these effects, suggesting ADAM10 proteases induce release of sCX3CL1 from stimulated human astrocytes. A p38 MAPK inhibitor also attenuated the levels of sCX3CL1 upon treatment with IL-1β, TNF-α or IFN-γ. In addition, an IKKβ inhibitor significantly reduced the levels of sCX3CL1 induced by IL-1β or TNF-α in a concentration-dependent manner, suggesting a role for the NF-kB pathway.ConclusionsIn conclusion, this study shows that the release of soluble astrocytic fractalkine is regulated by ADAM10 proteases with p38 MAPK also playing a role in the fractalkine shedding event. These findings are important for understanding the role of CX3CL1 in healthy and stimulated astrocytes and may benefit our understanding of this pathway in neuro-inflammatory and neurodegenerative diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0659-7) contains supplementary material, which is available to authorized users.

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“…It is currently marketed as Gilenya for use in multiple sclerosis patients to reduce the relapse rate and lessen disease progression. In vitro studies show that fingolimod, when added 1 hr before psychosine, was able to attenuate psychosine‐induced death of astrocytes and lessen decreases of mitochondria membrane potential in astrocytes (O'Sullivan and Dev, ). Fingolimod also reduced psychosine‐elicited demyelination in a cerebellar slice preparation (O'Sullivan and Dev, ).…”

Section: Biosynthesis Pathway Of Galactosylceramidementioning

confidence: 99%

Substrate reduction therapy for Krabbe's disease

Sands

Levine

2016

J of Neuroscience Research

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Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose‐sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used. Unfortunately, an inhibitor for the final step of galactosylceramide biosynthesis, i.e., UDP glycosyltransferase 8 (a.k.a. UDP‐galactose ceramide galactosyltransferase), has not been found. Approaches that inhibit an earlier biosynthetic step or that lessen the substrate burden by other means, such as genetic manipulations, have been tested in the twitcher mouse model of KD. Either as a stand‐alone therapy or in combination with other approaches, SRT slowed the disease course, indicating that this approach has potential therapeutic value. For instance, in individuals with adult‐onset disease, SRT theoretically could lessen the production of substrates so that residual enzymatic activity could adequately manage the lower substrate burden. In more severe forms of disease, SRT theoretically could be part of a combination therapy. However, SRT has the potential to impair normal function by reducing the synthesis of galactosylceramide to levels that impede myelin function, or SRT could have other deleterious effects. Thus, multiple issues need to be resolved before this approach is ready for testing in humans. © 2016 Wiley Periodicals, Inc.

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Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

Cited by 40 publications

References 51 publications

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Inhibition of Piezo1 attenuates demyelination in the central nervous system

Fractalkine shedding is mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes

Substrate reduction therapy for Krabbe's disease

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