Central nervous system myelin: structure, synthesis and assembly

Aggarwal, Sandeep; Yurlova, Larisa; Simons, Mikael

doi:10.1016/j.tcb.2011.06.004

Cited by 237 publications

(196 citation statements)

References 81 publications

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Section: Introductionmentioning

confidence: 99%

“…The membrane sheets of myelin are densely packed, resulting in the extrusion of cytosolic elements and in the formation of a lipid-rich, insulating sheath that enables the acceleration of nerve impulses. A mature myelin sheath can be morphologically divided into compact and non-compact myelin, of which the latter has a higher cytosolic content and further contains several subcompartments, such as the abaxonal and adaxonal layers, as well as the paranodal loops [1,2] .Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .…”

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confidence: 99%

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The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Raasakka

Kursula

2014

Neurosci. Bull.

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The membrane-anchored myelin enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) was discovered in the early 1960s and has since then troubled scientists with its peculiar catalytic activity and high expression levels in the central nervous system. Despite decades of research, the actual physiological relevance of CNPase has only recently begun to unravel. In addition to a role in myelination, CNPase is also involved in local adenosine production in traumatic brain injury and possibly has a regulatory function in mitochondrial membrane permeabilization. Although research focusing on the CNPase phosphodiesterase activity has been helpful, several open questions concerning the protein function in vivo remain unanswered. This review is focused on past research on CNPase, especially in the fields of structural biology and enzymology, and outlines the current understanding regarding the biochemical and physiological signifi cance of CNPase, providing ideas and directions for future research.Keywords: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; calmodulin; central nervous system; cytoskeleton; myelin proteins; RNA ·Review· IntroductionMyelin is a specialized multilamellar structure, which is wrapped around neuronal axons by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). The membrane sheets of myelin are densely packed, resulting in the extrusion of cytosolic elements and in the formation of a lipid-rich, insulating sheath that enables the acceleration of nerve impulses. A mature myelin sheath can be morphologically divided into compact and non-compact myelin, of which the latter has a higher cytosolic content and further contains several subcompartments, such as the abaxonal and adaxonal layers, as well as the paranodal loops [1,2] .Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .Several myelin proteins have delicately regulated expression levels and functions. Past research using cell culture and animal models have outlined the importance of various proteins in demyelination -a situation where myelin undergoes morphological changes and loss [6] .Demyelination causes neurological disorders, including multiple sclerosis (MS), Charcot-Marie-Tooth disease, and leukodystrophies, such as Pelizaeus-Merzbacher disease [7][8][9][10] .2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)is one of the most abundant proteins in CNS myelin and a possible auto-antigen in MS [4,11] . The high expression levels of CNPase, together with its rather unusual enzymatic after the initial di...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Raasakka

Kursula

2014

Neurosci. Bull.

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“…In nearly all vertebrates, mature OLGs extend membrane processes, which concentrically wrap segments of the axon forming the multilamellar structure of myelin during late foetal and early postnatal stages [1][2][3][4][5][6]. The CNS myelin, although mostly composed of lipids, possesses many fundamental proteins which are essential for proper structural and functional integrity of the sheath (reviewed by [7]).…”

Section: Introductionmentioning

confidence: 99%

Classic 18.5- and 21.5-kDa Myelin Basic Protein Isoforms Associate with Cytoskeletal and SH3-Domain Proteins in the Immortalized N19-Oligodendroglial Cell Line Stimulated by Phorbol Ester and IGF-1

et al. 2012

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The 18.5-kDa classic myelin basic protein (MBP) is an intrinsically disordered protein arising from the Golli (Genes of Oligodendrocyte Lineage) gene complex and is responsible for compaction of the myelin sheath in the central nervous system. This MBP splice isoform also has a plethora of post-translational modifications including phosphorylation, deimination, methylation, and deamidation, that reduce its overall net charge and alter its protein and lipid associations within oligodendrocytes (OLGs). It was originally thought that MBP was simply a structural component of myelin; however, additional investigations have demonstrated that MBP is multifunctional, having numerous protein-protein interactions with Ca 2+ -calmodulin, actin, tubulin, and proteins with SH3-domains, and it can tether these proteins to a lipid membrane in vitro. Here, we have examined cytoskeletal interactions of classic 18.5-kDa MBP, in vivo, using early developmental N19-OLGs transfected with fluorescently-tagged MBP, actin, tubulin, and zonula occludens 1 (ZO-1). We show that MBP redistributes to distinct 'membrane-ruffled' regions of the plasma membrane where it co-localizes with actin and tubulin, and with the SH3-domaincontaining proteins cortactin and ZO-1, when stimulated with PMA, a potent activator of the protein kinase C pathway. Moreover, using phospho-specific antibody staining, we show an increase in phosphorylated Thr98 MBP (human sequence numbering) in membrane-ruffled OLGs. CIHR Author ManuscriptCIHR Author Manuscript CIHR Author ManuscriptPreviously, Thr98 phosphorylation of MBP has been shown to affect its conformation, interactions with other proteins, and tethering of other proteins to the membrane in vitro. Here, MBP and actin were also co-localized in new focal adhesion contacts induced by IGF-1 stimulation in cells grown on laminin-2. This study supports a role for classic MBP isoforms in cytoskeletal and other protein-protein interactions during membrane and cytoskeletal remodeling in OLGs.

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“…4,5 The process of myelination accelerates during infancy and will be pursued until adolescence. Brain myelin formation during development is initiated by, as yet, poorly identified signals from axons to oligodendrocytes.…”

Section: Introductionmentioning

confidence: 99%

NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications

et al. 2012

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One of the key signals regulating peripheral myelin formation by Schwann cell is the activation of the transcription factor NF-jB. Yet, whether NF-jB exerts similar functions in central myelin formation by oligodendrocytes remains largely unknown. We previously reported white matter abnormalities with unusual discordance between T2 and FLAIR sequences in a patient with intellectual disability and defective NF-jB signalling. These observations prompted us to hypothesise that NF-jB signalling may have a role in the axon myelination process of central neurons. We report here on five male patients with Xq28 duplications encompassing MECP2, three of which presented white matter anomalies on brain MRI. Array-CGH and FISH analyses demonstrated that brain abnormalities correlate with additional copies of the IKBKG, a gene encoding a key regulator of NF-jB activation. Quantitative RT-PCR experiments and jB-responsive reporter gene assays provide evidence that IKBKG overexpression causes impaired NF-jB signalling in skin fibroblasts derived from patients with white matter anomalies. These data further support the role of NF-jB signalling in astroglial cells for normal myelin formation of the central nervous system.

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Central nervous system myelin: structure, synthesis and assembly

Cited by 237 publications

References 81 publications

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Classic 18.5- and 21.5-kDa Myelin Basic Protein Isoforms Associate with Cytoskeletal and SH3-Domain Proteins in the Immortalized N19-Oligodendroglial Cell Line Stimulated by Phorbol Ester and IGF-1

NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications

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