Expression of the ALS-Causing Variant hSOD1G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

Meister, Sabrina; Storck, Steffen E.; Hameister, Erik; Behl, Christian; Weggen, Sascha; Clement, Albrecht M.; Pietrzik, Claus U.

doi:10.1038/jcbfm.2015.57

Cited by 24 publications

(15 citation statements)

References 47 publications

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“…Although the disruption of the BSCB in ALS has been previously reported ( Garbuzova-Davis et al, 2007a , 2007b ; Zhong et al, 2008 ), the nature of the primum movens has remained debated: Is BSCB impairment driven by MN dysfunction or is it a MN-independent event? Some (controversial) evidence has pointed toward an MN-independent origin: Endothelial cells expressing mutant SOD1 in vitro display a cell-autonomous disruption of TJs because of the misfolded protein itself ( Meister et al, 2015 ). At the same time, endothelial cell–selective excision of the mutant SOD1 transgene does not prevent the breakdown of the BSCB nor affect the survival of the transgenic mice ( Zhong et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the driver(s) of BSCB disruption in ALS and its ultimate impact on disease progression are still debated. It has been hypothesized that damage of the BSCB may arise as a cell autonomous consequence of mutant SOD1 accumulation in endothelial cells: endothelial cells isolated from SOD1 G93A mice and immortalized mouse endothelial cells expressing the human G93A mutant SOD1 display reduced levels of claudin-5 (CLN-5) and decreased transendothelial resistance (Meister et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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Blood–spinal cord barrier (BSCB) disruption is thought to contribute to motoneuron (MN) loss in amyotrophic lateral sclerosis (ALS). It is currently unclear whether impairment of the BSCB is the cause or consequence of MN dysfunction and whether its restoration may be directly beneficial. We revealed that SOD1G93A, FUSΔNLS, TDP43G298S, and Tbk1+/− ALS mouse models commonly shared alterations in the BSCB, unrelated to motoneuron loss. We exploit PSAM/PSEM chemogenetics in SOD1G93A mice to demonstrate that the BSCB is rescued by increased MN firing, whereas inactivation worsens it. Moreover, we use DREADD chemogenetics, alone or in multiplexed form, to show that activation of Gi signaling in astrocytes restores BSCB integrity, independently of MN firing, with no effect on MN disease markers and dissociating them from BSCB disruption. We show that astrocytic levels of the BSCB stabilizers Wnt7a and Wnt5a are decreased in SOD1G93A mice and strongly enhanced by Gi signaling, although further decreased by MN inactivation. Thus, we demonstrate that BSCB impairment follows MN dysfunction in ALS pathogenesis but can be reversed by Gi-induced expression of astrocytic Wnt5a/7a.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

et al. 2020

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“…In peripheral nerves, claudin‐5 is present in endothelial cells of endoneurial vessels, as well as mesaxons and Schmidt–Lantermann incisures . In the spinal cord, claudin‐5 is reduced (e.g., in amyotrophic lateral sclerosis via the β‐catenin/AKT/FOXO1 pathway, and in hSOD G93A in transgenic endothelial cells). In CCI and SNI neuropathy, we observed that claudin‐5 mRNA in whole lumbar spinal cord and claudin‐5 immunoreactivity in spinal cord capillaries are reduced.…”

Section: Discussionmentioning

confidence: 99%

Blood–spinal cord barrier breakdown and pericyte deficiency in peripheral neuropathy

Sauer

Kirchner

Yang

et al. 2017

Annals of the New York Academy of Sciences

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The blood-spinal cord barrier (BSCB) prevents leakage of molecules, such as pronociceptive mediators, into the spinal cord, but its role in the pathophysiology of neuropathic pain is not completely understood. Rats with chronic constriction injury (CCI) develop mechanical allodynia, thermal hypersensitivity, and reduced motor performance (Rota-Rod test) compared with sham-injured mice-similar to mice with spared nerve injury (SNI). The BSCB becomes permeable for small and large tracers 1 day after nerve ligation. Messenger RNA (mRNA) expression of tight junction proteins (TJPs) occludin, claudin-1, claudin-5, claudin-19, tricellulin, and ZO-1 significantly declines 7-14 days after CCI or SNI. ZO-1 and occludin are reduced in the cell membrane. In capillaries isolated from the spinal cord, immunoreactivity of claudin-5 and ZO-1 is fainter. In parallel, the number of platelet-derived growth factor receptor β (PDGF-β) and CD13 pericytes in the spinal cord drops. Reduced levels of cytosolic transcription factors like β-catenin, but not SMAD4 and SLUG, could account for reduced TJP mRNA. In summary, neuropathy-induced allodynia/hypersensitivity is accompanied by a loss of pericytes in the spinal cord and a leaky BSCB. A better understanding of these pathways and mechanisms in neuropathic pain might foster the design of novel treatments to maintain spinal cord homeostasis.

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“…Additionally, for bEnd.3 cells, the permeability to [C 14 ]-inulin (Perkin-Elmer, Waltham, MA, USA) was analyzed as described previously. 19…”

Section: Methodsmentioning

confidence: 99%

Meprin β: A novel regulator of blood–brain barrier integrity

Gindorf

Storck

Ohler

et al. 2020

J Cereb Blood Flow Metab

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The metalloprotease meprin β (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood–brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [14C]-inulin. Analysis of global Mep1b knock-out (Mep1b−/−) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b−/− mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.

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Expression of the ALS-Causing Variant hSOD1^G93A Leads to an Impaired Integrity and Altered Regulation of Claudin-5 Expression in an in Vitro Blood–Spinal Cord Barrier Model

Cited by 24 publications

References 47 publications

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS

Blood–spinal cord barrier breakdown and pericyte deficiency in peripheral neuropathy

Meprin β: A novel regulator of blood–brain barrier integrity

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