Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis

Qosa, Hisham; Lichter, Jessica; Sarlo, Mark; Markandaiah, Shashirekha S.; McAvoy, Kevin; Richard, Jean Philippe; Jablonski, Michael; Maragakis, Nicholas J.; Pasinelli, Piera; Trotti, Davide

doi:10.1002/glia.23003

Cited by 66 publications

(79 citation statements)

References 63 publications

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“…Although the underlying connection between different genetic forms of ALS is complex and at this time unclear, this work indicates that strategies targeting astrocyte contributions to disease may be useful for a variety of ALS cases. Although future work must be done to confirm these findings in vivo and, eventually in patients, we recently confirmed the clinical relevance of our findings showing that in a patient‐derived in vitro model of the blood–brain‐barrier, iPSC‐derived astrocytes from a mutFUS patient, drive drug‐efflux transporter mediated pharmacoresistance through TNFα (Qosa et al, 2016). Thus, underscoring the role of TNFα in driving mutFUS‐ALS through astrocytes and identifying TNFα as an important therapeutic target in this form of the disease.…”

Section: Discussionsupporting

confidence: 74%

“…Chimeric mice in which mutant SOD1 was selectively deleted in astrocytes showed substantially slowed disease progression (Yamanaka et al, 2008) while both rodent and human patient‐derived astrocytes have been shown to play a toxic role through the release of, yet identified, soluble factors [reviewed (Haidet‐Phillips et al, 2011; Lasiene and Yamanaka, 2011). Furthermore, we recently showed that ALS astrocytes, including mutFUS expressing patient astrocytes, drive up‐regulation of the multidrug resistance transporter P‐Glycoprotein (P‐gp) in endothelial cells of the blood‐brain barrier (Qosa et al, 2016). Astrocytes participate in disease also through a “loss of function” [reviewed (Maragakis and Rothstein, 2006)] as demonstrated by several human and rodent studies that have observed defects and/or loss of astrocytic glutamate transporter EAAT2/GLT1 for several ALS subtypes including SOD1‐ALS (Benkler, Ben‐Zur, Barhum, & Offen, 2013; Howland et al, 2002) sALS (Lin et al, 1998), and C9orf72‐ALS (Kwon et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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“…Furthermore, in mixed neuron/astrocyte cultures subjected to oxygen-glucose deprivation, astrocytes are the sole locus for Nrf2 activation in response to oxidative stress [42, 43]. Interestingly, a new study has shown that astrocytes with mutant SOD1 increase P-glycoprotein in endothelial cells in vitro [44]. Moreover, astrocytic Nrf2 activation helps to prevent oligodendrocyte loss and demyelination in an animal model of multiple sclerosis [45].…”

Section: Discussionmentioning

confidence: 99%

(−)-Epicatechin, a Natural Flavonoid Compound, Protects Astrocytes Against Hemoglobin Toxicity via Nrf2 and AP-1 Signaling Pathways

Lan

Han

et al. 2016

Mol Neurobiol

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(−)-Epicatechin is a brain-permeable, natural product found at high concentrations in green tea and cocoa. Our previous research has shown that (−)-epicat-echin treatment reduces hemorrhagic stroke injury via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in vivo. However, the mechanism of action of this compound in modulation of oxidant stress and in protection against hemoglobin-induced astrocyte injury is unclear. Therefore, we explored the cellular and molecular mechanisms that underlie these protective effects in vitro. Mouse primary astrocytes isolated from wild-type mice and Nrf2 knockout (KO) mice were preconditioned with hemoglobin to simulate intracerebral hemorrhage (ICH) in vitro. Effects of (−)-epicate-chin were measured by Western blotting, immunostaining, MTT assay, and reactive oxidant stress (ROS) assay. (−)-Epicatechin increased Nrf2 nuclear accumulation and cytoplasmic levels of superoxide dismutase 1 (SOD1) in wild-type astrocytes but did not increase SOD1 expression in Nrf2 knockout (KO) astrocytes. Furthermore, (−)-epicatechin treatment did not alter heme oxygenase 1 (HO1) expression in wild-type astrocytes after hemoglobin exposure, but it did decrease HO1 expression in similarly treated Nrf2 KO astrocytes. In both wild-type and Nrf2 KO astrocytes, (−)-epicatechin suppressed phosphorylated JNK and nuclear expression of JNK, c-jun, and c-fos, indicating that inhibition of activator protein-1 (AP-1) activity by (−)-epicatechin is Nrf2-independent. These novel findings indicate that (−)-epicatechin protects astrocytes against hemoglobin toxicity through upregulation of Nrf2 and inhibition of AP-1 activity. These cellular and molecular effects may partially explain the cerebroprotection as we previously observed for (−)-epicatechin in animal models of ICH.

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“…ABCB1, one of the members of the ABC transporter family involved in multidrug resistance, is upregulated in endothelial cells of the brain capillaries in ALS. In blood-brain barrier models, the expression of mutant hSOD1 and mutant FUS in astrocytes drives ABCB1 upregulation in endothelial cells [201]. Thus, the potential role of astrocytes affecting drug bioavailability may need to be addressed in order to implement effective drug therapies in ALS.…”

Section: Therapeutic Potential Of Astrocytesmentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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Astrocytes drive upregulation of the multidrug resistance transporter ABCB1 (P‐Glycoprotein) in endothelial cells of the blood–brain barrier in mutant superoxide dismutase 1‐linked amyotrophic lateral sclerosis

Cited by 66 publications

References 63 publications

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

(−)-Epicatechin, a Natural Flavonoid Compound, Protects Astrocytes Against Hemoglobin Toxicity via Nrf2 and AP-1 Signaling Pathways

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

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