Please use this identifier to cite or link to this item:
https://hdl.handle.net/10216/110350
Author(s): | Silva, TF Eira, J Lopes, AT Malheiro, AR Sousa, V Luoma, A Avila, RL Wanders, RJ Just, WW Kirschner, DA Sousa, MM Brites, P |
Title: | Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
Publisher: | American Society for Clinical Investigation |
Issue Date: | 2014 |
Abstract: | 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. |
Subject: | Animals Cell Differentiation/physiology Chondrodysplasia Punctata Rhizomelic/etiology Chondrodysplasia Punctata Rhizomelic/pathology Chondrodysplasia Punctata Rhizomelic/physiopathology Female Glycogen Synthase Kinase 3/antagonists & inhibitors Glycogen Synthase Kinase 3/metabolism Glycogen Synthase Kinase 3 beta Humans Male Mice Mice Knockout Mice Neurologic Mutants Models Neurological Myelin Basic Protein/metabolism Myelin Sheath/physiology Nerve Regeneration Peripheral Nervous System/cytology Peripheral Nervous System/physiology Peroxisomal Targeting Signal 2 Receptor Plasmalogens/physiology Proto-Oncogene Proteins c-akt/metabolism Receptors, Cytoplasmic and Nuclear/deficiency Receptors, Cytoplasmic and Nuclear/genetics Schwann Cells/cytology Schwann Cells/physiology Signal Transduction |
URI: | http://hdl.handle.net/10216/110350 |
Source: | The Journal of Clinical Investigation, vol. 124(6), p. 2560-70 |
Related Information: | info:eu-repo/grantAgreement/FCT/5876-PPCDTI/112406/PT info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F88160%2F2012/PT |
Document Type: | Artigo em Revista Científica Internacional |
Rights: | openAccess |
Appears in Collections: | I3S - Artigo em Revista Científica Internacional |
Files in This Item:
File | Description | Size | Format | |
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FerreiraSilva2014.pdf | 4.33 MB | Adobe PDF | View/Open | |
FerreiraSilva2014SupMat.pdf | 1.33 MB | Adobe PDF | View/Open |
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