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Martin E Schwab - One of the best experts on this subject based on the ideXlab platform.
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sequential loss of Myelin Proteins during wallerian degeneration in the human spinal cord
Brain, 2004Co-Authors: A Buss, Katrin Pech, Doron Merkler, B A Kakulas, Didier Martin, Jean Schoenen, J Noth, Martin E Schwab, G BrookAbstract:Axons undergo Wallerian degeneration (WD) distal to a point of injury. In the lesioned PNS, WD may be followed by successful axonal regeneration and functional recovery. However, in the lesioned mammalian CNS, there is no significant axonal regeneration. Myelin-associated Proteins (MAPs) have been shown to play significant roles in preventing axonal regeneration in the CNS. Since relatively little is known about such events in human CNS pathologies, we performed an immunohistochemical investigation on the temporal changes of four MAPs during WD in post-mortem spinal cords of 22 patients who died 2 days to 30 years after either cerebral infarction or traumatic spinal cord injury. In contrast to experimental studies in rats, the loss of Myelin sheaths is greatly delayed in humans and continues slowly over a number of years. However, in agreement with animal data, a sequential loss of Myelin Proteins was found which was dependent on their location within the Myelin sheath. Myelin Proteins situated on the peri-axonal membrane were the first to be lost, the time course correlating with the loss of axonal markers. Proteins located within compact Myelin or on the outer Myelin membrane were still detectable 3 years after injury in degenerating fibre tracts, long after the disappearance of the corresponding axons. The persistence of axon growth-inhibitory Proteins such as NOGO-A in degenerating nerve fibre tracts may contribute to the maintenance of an environment that is hostile to axon regeneration, long after the initial injury. The present data highlight the importance of correlating the well documented, lesion-induced changes that take place in controlled laboratory investigations with those that take place in the clinical domain.
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sequential loss of Myelin Proteins during wallerian degeneration in the rat spinal cord
Glia, 2003Co-Authors: A Buss, Martin E SchwabAbstract:Axotomy of nerve fibers leads to the subsequent degeneration of their distal part, a process termed Wallerian degeneration (WD). While WD in the peripheral nervous system is usually followed by regeneration of the lesioned axons, central nervous system (CNS) neurons are generally unable to regrow. In this study, we investigated the process of WD in the dorsal columns of the rat spinal cord rostral to a mid-thoracic lesion. We confirm earlier studies describing a very delayed microglial and an early and sustained astroglial reaction finally leading to scar formation. Interestingly, we found a differential time course in the loss of Myelin Proteins depending on their location. Proteins situated on the periaxonal Myelin membrane such as Myelin associated glycoprotein disappeared early, within a few days after lesion, concomitantly with cytoskeletal axonal Proteins, whereas compact Myelin and outer Myelin membrane Proteins such as MBP and Nogo-A remained for long intervals in the degenerating tracts. Two distinct mechanisms are probably responsible for this difference: processes of protein destruction emanating from and initially probably located in the axon act on a time scale of 1-3 days. In contrast, the bulk of Myelin destruction is due to phagocytosis known to be slow, prolonged, and inefficient in the CNS. These results may also have implications for future intervention strategies aiming at enhancing CNS regeneration.
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inhibition of pc12 cell attachment and neurite outgrowth by detergent solubilized cns Myelin Proteins
European Journal of Neuroscience, 1995Co-Authors: Beatrix P Rubin, Adrian Spillmann, Christine E Bandtlow, Rainer Hillenbrand, Flavio Keller, Martin E SchwabAbstract:Adhesion and neurite outgrowth of PC12 cells, as well as the spreading of 3T3 fibroblasts, were inhibited in a dose dependent manner by detergent solubilized mouse central nervous system Myelin Proteins as a tissue culture substrate. These inhibitory effects could be neutralized by the monoclonal antibody IN-1 directed against the neurite growth inhibiting Proteins NI-35 and NI-250. Separation of the detergent soluble Proteins of bovine spinal cord by an anion exchange column showed that the peaks of inhibitory activity for the two cell lines overlapped, such that the PC12 cells were inhibited by a larger number of fractions comprising those inhibitory for 3T3 cells. Neurite outgrowth of PC12 cells was not influenced by the Myelin associated glycoprotein, MAG.
Petri Kursula - One of the best experts on this subject based on the ideXlab platform.
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influence of Myelin Proteins on the structure and dynamics of a model membrane with emphasis on the low temperature regime
Journal of Chemical Physics, 2014Co-Authors: W Knoll, Petri Kursula, Judith Peters, Y Gerelli, F NataliAbstract:Myelin is an insulating, multi-lamellar membrane structure wrapped around selected nerve axons. Increasing the speed of nerve impulses, it is crucial for the proper functioning of the vertebrate nervous system. Human neurodegenerative diseases, such as multiple sclerosis, are linked to damage to the Myelin sheath through deMyelination. Myelin exhibits a well defined subset of Myelin-specific Proteins, whose influence on membrane dynamics, i.e., Myelin flexibility and stability, has not yet been explored in detail. In a first paper [W. Knoll, J. Peters, P. Kursula, Y. Gerelli, J. Ollivier, B. Deme, M. Telling, E. Kemner, and F. Natali, Soft Matter 10, 519 (2014)] we were able to spotlight, through neutron scattering experiments, the role of peripheral nervous system Myelin Proteins on membrane stability at room temperature. In particular, the Myelin basic protein and peripheral Myelin protein 2 were found to synergistically influence the membrane structure while keeping almost unchanged the membrane mobility. Further insight is provided by this work, in which we particularly address the investigation of the membrane flexibility in the low temperature regime. We evidence a different behavior suggesting that the proton dynamics is reduced by the addition of the Myelin basic protein accompanied by negligible membrane structural changes. Moreover, we address the importance of correct sample preparation and characterization for the success of the experiment and for the reliability of the obtained results.
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lipid membrane association of Myelin Proteins and peptide segments studied by oriented and synchrotron radiation circular dichroism spectroscopy
Journal of Physical Chemistry B, 2013Co-Authors: Gopinath Muruganandam, Jochen Burck, Anne S Ulrich, Inari Kursula, Petri KursulaAbstract:Myelin-specific Proteins are either integral or peripheral membrane Proteins that, in complex with lipids, constitute a multilayered proteolipid membrane system, the Myelin sheath. The Myelin sheath surrounds the axons of nerves and enables rapid conduction of axonal impulses. Myelin Proteins interact intimately with the lipid bilayer and play crucial roles in the assembly, function, and stability of the Myelin sheath. Although Myelin Proteins have been investigated for decades, their structural properties upon membrane surface binding are still largely unknown. In this study, we have used simplified model systems consisting of synthetic peptides and membrane mimics, such as detergent micelles and/or lipid vesicles, to probe the conformation of peptides using synchrotron radiation circular dichroism spectroscopy (SRCD). Additionally, oriented circular dichroism spectroscopy (OCD) was employed to examine the orientation of Myelin peptides in macroscopically aligned lipid bilayers. Various representative pe...
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Membrane Interactions, Intrinsic Disorder, and Unknown Functions of Myelin Proteins
Biophysical Journal, 2013Co-Authors: Maryna Chukhlieb, Huijong Han, Matti Myllykoski, Saara Laulumaa, Arne Raasakka, Salla Ruskamo, Chaozhan Wang, Petri KursulaAbstract:The Myelin sheath is a unique membrane, tightly wrapped around selected axons in the vertebrate nervous system. The multilayered Myelin proteolipid membrane contains a specific set of Proteins, many of which share no homology with other known Proteins. We are interested in the structure, function, interactions, and dynamics of Myelin Proteins and use multidisciplinary methods to study these relationships. We have solved crystal structures of Myelin-specific Proteins, characterized their membrane-binding properties, and initiated experiments to pinpoint details of protein dynamics. Among our most recent results are a comprehensive X-ray crystal structure-based characterization of the reaction cycle of the Myelin enzyme CNPase, the identification of several Myelin-specific Proteins as intrinsically disordered molecules, and the analysis of molecular dynamics in Myelin Proteins and the lipid bilayers they interact with by neutron scattering. All the results will be important in understanding the formation of the Myelin membrane multilayer, as well as the roles the Myelin Proteins play in Myelination and Myelin-related diseases.
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conformations of peptides derived from Myelin specific Proteins in membrane mimetic conditions probed by synchrotron radiation cd spectroscopy
Amino Acids, 2012Co-Authors: Matti Myllykoski, Peter Baumgartel, Petri KursulaAbstract:Myelin is a tightly packed membrane multilayer in the nervous system, which harbours a specific set of quantitatively major Proteins. All these Proteins interact with the lipid bilayer, being either peripheral or integral membrane Proteins. In this study, we examined the conformational properties of peptides from the Myelin Proteins P0, CNPase, MOBP, P2 and MOG, using trifluoroethanol and micelles of different detergents as membrane-like mimics. The peptides showed significant differences in their folding under the employed conditions, as evidenced by synchrotron radiation circular dichroism spectroscopy. Our experiments provide new structural information on the interactions between Myelin Proteins and membranes, using a simplified model system of synthetic peptides and micelles.
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Structure and function of the Myelin Proteins: current status and perspectives in relation to multiple sclerosis.
Current Medicinal Chemistry, 2005Co-Authors: Andreas G. Tzakos, Petri Kursula, Anastassios N. Troganis, Vassiliki Theodorou, Theodore Tselios, Christos Svarnas, John Matsoukas, Vasso Apostolopoulos, Ioannis P. GerothanassisAbstract:Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by deMyelination and loss of neurological function, local macrophage infiltrate and neuroantigenspecific CD4+T cells. MS arises from complex interactions between genetic, immunological, infective and biochemical mechanisms. Although the circumstances of MS etiology remain hypothetical, one persistent theme involves immune system recognition of Myelin-specific antigens derived from Myelin basic protein, the most abundant extrinsic Myelin membrane protein, and/or another equally suitable Myelin protein or lipid. Knowledge of the biochemical and physico-chemical properties of Myelin Proteins and lipids, particularly their composition, organization, structure and accessibility with respect to the compacted Myelin multilayers, becomes central to understanding how and why Myelin-specific antigens become selected during the development of MS. This review focuses on the current understanding of the molecular basis of MS with emphasis: (i) on the physical-chemical properties, organization, morphology, and accessibility of the Proteins and lipids within the Myelin multilayers; (ii) on the structure-function relationships and characterization of the Myelin Proteins relevant to the manifestation and evolution of MS; (iii) on conformational relationships between Myelin epitopes which might become selected during the development of MS; (iv) on the structure of MHC/HLA in complex with MBP peptides as well as with TCR, which is crucial to the understanding of the pathogenesis of MS with the ultimate goal of designed antigen-specific treatments.
A Buss - One of the best experts on this subject based on the ideXlab platform.
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sequential loss of Myelin Proteins during wallerian degeneration in the human spinal cord
Brain, 2004Co-Authors: A Buss, Katrin Pech, Doron Merkler, B A Kakulas, Didier Martin, Jean Schoenen, J Noth, Martin E Schwab, G BrookAbstract:Axons undergo Wallerian degeneration (WD) distal to a point of injury. In the lesioned PNS, WD may be followed by successful axonal regeneration and functional recovery. However, in the lesioned mammalian CNS, there is no significant axonal regeneration. Myelin-associated Proteins (MAPs) have been shown to play significant roles in preventing axonal regeneration in the CNS. Since relatively little is known about such events in human CNS pathologies, we performed an immunohistochemical investigation on the temporal changes of four MAPs during WD in post-mortem spinal cords of 22 patients who died 2 days to 30 years after either cerebral infarction or traumatic spinal cord injury. In contrast to experimental studies in rats, the loss of Myelin sheaths is greatly delayed in humans and continues slowly over a number of years. However, in agreement with animal data, a sequential loss of Myelin Proteins was found which was dependent on their location within the Myelin sheath. Myelin Proteins situated on the peri-axonal membrane were the first to be lost, the time course correlating with the loss of axonal markers. Proteins located within compact Myelin or on the outer Myelin membrane were still detectable 3 years after injury in degenerating fibre tracts, long after the disappearance of the corresponding axons. The persistence of axon growth-inhibitory Proteins such as NOGO-A in degenerating nerve fibre tracts may contribute to the maintenance of an environment that is hostile to axon regeneration, long after the initial injury. The present data highlight the importance of correlating the well documented, lesion-induced changes that take place in controlled laboratory investigations with those that take place in the clinical domain.
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sequential loss of Myelin Proteins during wallerian degeneration in the rat spinal cord
Glia, 2003Co-Authors: A Buss, Martin E SchwabAbstract:Axotomy of nerve fibers leads to the subsequent degeneration of their distal part, a process termed Wallerian degeneration (WD). While WD in the peripheral nervous system is usually followed by regeneration of the lesioned axons, central nervous system (CNS) neurons are generally unable to regrow. In this study, we investigated the process of WD in the dorsal columns of the rat spinal cord rostral to a mid-thoracic lesion. We confirm earlier studies describing a very delayed microglial and an early and sustained astroglial reaction finally leading to scar formation. Interestingly, we found a differential time course in the loss of Myelin Proteins depending on their location. Proteins situated on the periaxonal Myelin membrane such as Myelin associated glycoprotein disappeared early, within a few days after lesion, concomitantly with cytoskeletal axonal Proteins, whereas compact Myelin and outer Myelin membrane Proteins such as MBP and Nogo-A remained for long intervals in the degenerating tracts. Two distinct mechanisms are probably responsible for this difference: processes of protein destruction emanating from and initially probably located in the axon act on a time scale of 1-3 days. In contrast, the bulk of Myelin destruction is due to phagocytosis known to be slow, prolonged, and inefficient in the CNS. These results may also have implications for future intervention strategies aiming at enhancing CNS regeneration.
G Brook - One of the best experts on this subject based on the ideXlab platform.
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sequential loss of Myelin Proteins during wallerian degeneration in the human spinal cord
Brain, 2004Co-Authors: A Buss, Katrin Pech, Doron Merkler, B A Kakulas, Didier Martin, Jean Schoenen, J Noth, Martin E Schwab, G BrookAbstract:Axons undergo Wallerian degeneration (WD) distal to a point of injury. In the lesioned PNS, WD may be followed by successful axonal regeneration and functional recovery. However, in the lesioned mammalian CNS, there is no significant axonal regeneration. Myelin-associated Proteins (MAPs) have been shown to play significant roles in preventing axonal regeneration in the CNS. Since relatively little is known about such events in human CNS pathologies, we performed an immunohistochemical investigation on the temporal changes of four MAPs during WD in post-mortem spinal cords of 22 patients who died 2 days to 30 years after either cerebral infarction or traumatic spinal cord injury. In contrast to experimental studies in rats, the loss of Myelin sheaths is greatly delayed in humans and continues slowly over a number of years. However, in agreement with animal data, a sequential loss of Myelin Proteins was found which was dependent on their location within the Myelin sheath. Myelin Proteins situated on the peri-axonal membrane were the first to be lost, the time course correlating with the loss of axonal markers. Proteins located within compact Myelin or on the outer Myelin membrane were still detectable 3 years after injury in degenerating fibre tracts, long after the disappearance of the corresponding axons. The persistence of axon growth-inhibitory Proteins such as NOGO-A in degenerating nerve fibre tracts may contribute to the maintenance of an environment that is hostile to axon regeneration, long after the initial injury. The present data highlight the importance of correlating the well documented, lesion-induced changes that take place in controlled laboratory investigations with those that take place in the clinical domain.
Daniel A Kirschner - One of the best experts on this subject based on the ideXlab platform.
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evolution of Myelin ultrastructure and the major structural Myelin Proteins
Brain Research, 2016Co-Authors: Hideyo Inouye, Daniel A KirschnerAbstract:Myelin sheaths, as the specialized tissue wrapping the nerve fibers in the central and peripheral nervous systems (CNS and PNS), are responsible for rapid conduction of electrical signals in these fibers. We compare the nerve Myelin sheaths of different phylogenetic origins-including mammal, rodent, bird, reptile, amphibian, lungfish, teleost, and elasmobranch-with respect to periodicities and inter-membrane separations at their cytoplasmic and extracellular appositions, and correlate these structural parameters with biochemical composition. P0 glycoprotein and P0-like Proteins are present in PNS of terrestrial species or land vertebrates (Tetrapod) and in CNS and PNS of aquatic species. Proteolipid protein (PLP) is a major component only in the CNS Myelin of terrestrial species and is involved in compaction of the extracellular apposition. The Myelin structures of aquatic garfish and lungfish, which contain P0-like protein both in CNS and PNS, are similar to those of terrestrial species, indicating that they may be transitional organisms between water and land species. This article is part of a Special Issue entitled SI: Myelin Evolution.
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folding and function of the Myelin Proteins from primary sequence data
Journal of Neuroscience Research, 1991Co-Authors: Hideyo Inouye, Daniel A KirschnerAbstract:Abstract To explain how the Myelin Proteins are involved in the organization and function of the Myelin sheath requires knowing their molecular structures. Except for P2 basic protein of PNS Myelin, however, their structures are not yet known. As an aid to predicting their molecular folding and possible functions, we have developed a FORTRAN program to analyze the primary sequence data for Proteins, and have applied this to the Myelin Proteins in particular. In this program, propensities for the secondary structure conformations as well as physical-chemical parameters are assigned to the amino acids and the pattern of these parameters is examined by calculating their average values, autocorrelation functions and Fourier transforms. To compare two Proteins, their sequences are aligned using a unitary scoring matrix, and homologies are searched by plotting a two-dimensional map of the correlation coefficients. Comparison of the corresponding Myelin basic Proteins (MBP) and P0 glycoProteins (P0) for rodent and shark showed that the conserved residues included most of the amino acids which were predicted to form the alpha or beta conformations, while the altered residues were mainly in the hydrophilic and turn or coil regions. In both rodent and shark the putative extracellular domain of P0 glycoprotein displayed consecutive peaks of beta propensity similar to that for the immunoglobulins, while the cytoplasmic domain showed alpha-beta-alpha folding. To trace the immunoglobulin fold along the P0 sequence, we compared the beta propensity curve of P0 with that of the immunoglobulin M603, whose three-dimensional structure has been determined. We propose that the flat beta-sheets of P0 are orientated parallel to the membrane surface to facilitate their homotypic interaction in the extracellular space. An extra beta-fold in the extracellular domain of shark P0 compared with rodent P0 was found, and this may result in a greater attraction between the apposed extracellular surfaces and may account for a smaller extracellular space as measured by x-ray diffraction. A computer search of the Myelin protein sequences for functional motifs revealed sites for N-glycosylation, phosphorylation, nucleotide binding, and certain enzyme activities. We note especially that there are potential nucleotide binding sites in proteolipid protein (PLP), MBP and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). This is consistent with the experimental observations that PLP acts like an ionophore or proton channel when reconstituted into planar lipid bilayers, MBP binds GTP, and CNP catalyzes in vitro the hydrolysis of 2',3'-nucleotides into corresponding 2'-nucleotides.
