Lithium enhances remyelination of peripheral nerves

Makoukji, Joelle; Belle, Morgane; Meffre, Delphine; Stassart, Ruth M.; Grenier, Julien; Shackleford, Ghjuvan’Ghjacumu; Fledrich, Robert; Fonte, Cosima; Branchu, Julien; Goulard, Marie; Waele, Catherine de; Charbonnier, Frédéric; Sereda, Michael W.; Baulieu, Étienne-Émile; Schumacher, Michaël; Bernard, Sophie; Massaad, Charbel

doi:10.1073/pnas.1121367109

Cited by 102 publications

(77 citation statements)

References 29 publications

(29 reference statements)

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“…In nerves from Gnpat-KO mice, we observed increased levels of Tyr216 phosphorylation and decreased levels of Ser9 phosphorylation, which, combined, indicate overtly active GSK3β (41). Lithium, a known inhibitor of GSK3β, can directly inhibit the kinase through Mg 2+ competition and can indirectly inhibit GSK3β by promoting further inhibition through Ser9 phosphorylation (42,43). Lithium administration to Gnpat-KO mice was able to normalize GSK3β phosphorylation status, induced the stimulation of Schwann cell differentiation, rescued the radial sorting defect, and improved myelination independently of the plasmalogen defect.…”

Section: Methodsmentioning

confidence: 96%

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Silva¹,

Eira²,

Lopes³

et al. 2014

J. Clin. Invest.

104

114

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Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.

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Section: Methodsmentioning

confidence: 96%

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Silva¹,

Eira²,

Lopes³

et al. 2014

J. Clin. Invest.

104

114

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“…We have shown that the selective inhibition of Wnt components by siRNA or dominant negative forms inhibits the expression of myelin genes in mouse Schwann cells (34,35). Moreover, the activation of Wnt signaling by recombinant Wnt ligands increases the transcription of myelin genes.…”

Section: Discussionmentioning

confidence: 99%

The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis

Luscan

Shackleford

Masliah‐Planchon

et al. 2014

Clinical Cancer Research

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Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies.Experimental Design: The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial-mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines.Results: The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active b-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann-mesenchymal transition.Conclusion: We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis. Clin Cancer Res; 20(2); 358-71. Ó2013 AACR.

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“…It is thought that this effect arises from the enhanced remyelination of peripheral nerves [11] and increased proliferation of neural progenitor cells [12] through the activation of the Wnt/ β-catenin signaling pathway following treatments with lithium compounds. Activation of this pathway through cell exposure to Li has been reported to promote osteoblastogenesis and inhibit osteoclastogenesis, leading to an increase in bone formation and volume in rats [13,14].…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of lithium-releasing silicate bioactive glasses and their scaffolds for bone repair

Miguez-Pacheco

Büttner

Maçon

et al. 2016

Journal of Non-Crystalline Solids

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Lithium enhances remyelination of peripheral nerves

Cited by 102 publications

References 29 publications

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination

The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis

Development and characterization of lithium-releasing silicate bioactive glasses and their scaffolds for bone repair

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