In addition to their role in providing myelin for rapid impulse propagation, the glia that ensheath long axons are required for the maintenance of normal axon transport and long-term survival. This presumably ancestral function seems to be independent of myelin membrane wrapping. Here, I propose that ensheathing glia provide trophic support to axons that are metabolically isolated, and that myelin itself might cause such isolation. This glial support of axonal integrity may be relevant for a number of neurological and psychiatric diseases.
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Herculano-Houzel, S., Mota, B. & Lent, R. Cellular scaling rules for rodent brains. Proc. Natl Acad. Sci. USA 103, 12138–12143 (2006).
Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998).
Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nature Genet. 33, 366–374 (2003).
Kassmann, C. M. et al. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Nature Genet. 39, 969–976 (2007).
Yin, X. et al. Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J. Neurosci. 18, 1953–1962 (1998).
Zalc, B. & Colman, D. R. Origins of vertebrate success. Science 288, 271–272 (2000).
Hildebrand, C., Remahl, S., Persson, H. & Bjartmar, C. Myelinated nerve fibres in the CNS. Prog. Neurobiol. 40, 319–384 (1993).
Hildebrand, C., Bowe, C. M. & Remahl, I. N. Myelination and myelin sheath remodelling in normal and pathological PNS nerve fibres. Prog. Neurobiol. 43, 85–141 (1994).
Perkins, G. A. et al. Electron tomographic analysis of cytoskeletal cross-bridges in the paranodal region of the node of Ranvier in peripheral nerves. J. Struct. Biol. 161, 469–480 (2008).
Rosenbluth, J. Multiple functions of the paranodal junction of myelinated nerve fibers. J. Neurosci. Res. 87, 3250–3258 (2009).
Salzer, J. L., Brophy, P. J. & Peles, E. Molecular domains of myelinated axons in the peripheral nervous system. Glia 56, 1532–1540 (2008).
Fields, R. D. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. Neuroscientist 14, 540–543 (2008).
Simons, M. & Trotter, J. Wrapping it up: the cell biology of myelination. Curr. Opin. Neurobiol. 17, 533–540 (2007).
Trapp, B. D. & Nave, K. A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).
Schiffmann, R. & van der Knaap, M. S. The latest on leukodystrophies. Curr. Opin. Neurol. 17, 187–192 (2004).
Suter, U. & Scherer, S. S. Disease mechanisms in inherited neuropathies. Nature Rev. Neurosci. 4, 714–726 (2003).
Fields, R. D. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 31, 361–370 (2008).
Ferguson, B., Matyszak, M. K., Esiri, M. M. & Perry, V. H. Axonal damage in acute multiple sclerosis lesions. Brain 120, 393–399 (1997).
Trapp, B. D. et al. Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).
Garbern, J. Y. et al. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125, 551–561 (2002).
Nave, K. A., Sereda, M. W. & Ehrenreich, H. Mechanisms of disease: inherited demyelinating neuropathies — from basic to clinical research. Nature Clin. Pract. Neurol. 3, 453–464 (2007).
Scherer, S. S. & Wrabetz, L. Molecular mechanisms of inherited demyelinating neuropathies. Glia 56, 1578–1589 (2008).
Pareyson, D., Scaioli, V. & Laura, M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med. 8, 3–22 (2006).
Griffin, J. W. & Watson, D. F. Axonal transport in neurological disease. Ann. Neurol. 23, 3–13 (1988).
Zipp, F. & Aktas, O. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci. 29, 518–527 (2006).
Neumann, H., Medana, I. M., Bauer, J. & Lassmann, H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 25, 313–319 (2002).
Smith, K. J. & Lassmann, H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 1, 232–241 (2002).
Trapp, B. D. & Stys, P. K. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280–291 (2009).
Waxman, S. G. Ions, energy and axonal injury: towards a molecular neurology of multiple sclerosis. Trends Mol. Med. 12, 192–195 (2006).
Craner, M. J. et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc. Natl Acad. Sci. USA 101, 8168–8173 (2004).
Stys, P. K., Waxman, S. G. & Ransom, B. R. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na+-Ca2+ exchanger. J. Neurosci. 12, 430–439 (1992).
Stys, P. K. Anoxic and ischemic injury of myelinated axons in CNS white matter: from mechanistic concepts to therapeutics. J. Cereb. Blood Flow Metab. 18, 2–25 (1998).
Salter, M. G. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438, 1167–1171 (2005).
Micu, I. et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439, 988–992 (2006).
Ouardouz, M. et al. Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors. Ann. Neurol. 65, 151–159 (2009).
Ouardouz, M. et al. Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors. Ann. Neurol. 65, 160–166 (2009).
Newman, T. A. et al. T-cell- and macrophage-mediated axon damage in the absence of a CNS-specific immune response: involvement of metalloproteinases. Brain 124, 2203–2214 (2001).
de Waegh, S. M., Lee, V. M. & Brady, S. T. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell 68, 451–463 (1992).
Sanchez, I., Hassinger, L., Paskevich, P. A., Shine, H. D. & Nixon, R. A. Oligodendroglia regulate the regional expansion of axon caliber and local accumulation of neurofilaments during development independently of myelin formation. J. Neurosci. 16, 5095–5105 (1996).
Inoue, Y., Nakamura, R., Mikoshiba, K. & Tsukada, Y. Fine structure of the central myelin sheath in the myelin deficient mutant Shiverer mouse, with special reference to the pattern of myelin formation by oligodendroglia. Brain Res. 219, 85–94 (1981).
Shine, H. D., Readhead, C., Popko, B., Hood, L. & Sidman, R. L. Morphometric analysis of normal, mutant, and transgenic CNS: correlation of myelin basic protein expression to myelinogenesis. J. Neurochem. 58, 342–349 (1992).
Rosenbluth, J. Central myelin in the mouse mutant shiverer. J. Comp. Neurol. 194, 639–648 (1980).
Andrews, H. et al. Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J. Neurosci. Res. 83, 1533–1539 (2006).
Brady, S. T. et al. Formation of compact myelin is required for maturation of the axonal cytoskeleton. J. Neurosci. 19, 7278–7288 (1999).
Saher, G. et al. High cholesterol level is essential for myelin membrane growth. Nature Neurosci. 8, 468–475 (2005).
Saher, G. et al. Cholesterol regulates the endoplasmic reticulum exit of the major membrane protein P0 required for peripheral myelin compaction. J. Neurosci. 29, 6094–6104 (2009).
Klugmann, M. et al. Assembly of CNS myelin in the absence of proteolipid protein. Neuron 18, 59–70 (1997).
Edgar, J. M. et al. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol. 166, 121–131 (2004).
Edgar, J. M. et al. Early ultrastructural defects of axons and axon-glia junctions in mice lacking expression of Cnp1. Glia 57, 1815–1824 (2009).
Rosenbluth, J., Nave, K. A., Mierzwa, A. & Schiff, R. Subtle myelin defects in PLP-null mice. Glia 54, 172–182 (2006).
Yin, X. et al. Evolution of a neuroprotective function of central nervous system myelin. J. Cell Biol. 172, 469–478 (2006).
Ferreirinha, F. et al. Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. J. Clin. Invest. 113, 231–242 (2004).
Tarrade, A. et al. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum. Mol. Genet. 15, 3544–3558 (2006).
Rasband, M. N. et al. CNP is required for maintenance of axon-glia interactions at nodes of Ranvier in the CNS. Glia 50, 86–90 (2005).
Garcia-Fresco, G. P. et al. Disruption of axo-glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons. Proc. Natl Acad. Sci. USA 103, 5137–5142 (2006).
Higuchi, M. et al. Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies. J. Neurosci. 25, 9434–9443 (2005).
Yazawa, I. et al. Mouse model of multiple system atrophy α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45, 847–859 (2005).
Zoller, I. et al. Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration. J. Neurosci. 28, 9741–9754 (2008).
Montag, D. et al. Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229–246 (1994).
Li, C. et al. Myelination in the absence of myelin-associated glycoprotein. Nature 369, 747–750 (1994).
Nguyen, T. et al. Axonal protective effects of the myelin-associated glycoprotein. J. Neurosci. 29, 630–637 (2009).
Zhou, L. & Griffin, J. W. Demyelinating neuropathies. Curr. Opin. Neurol. 16, 307–313 (2003).
Marrosu, M. G. et al. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology 50, 1397–1401 (1998).
Laura, M. et al. Rapid progression of late onset axonal Charcot-Marie-Tooth disease associated with a novel MPZ mutation in the extracellular domain. J. Neurol. Neurosurg. Psychiatry 78, 1263–1266 (2007).
Sousa, A. D. & Bhat, M. A. Cytoskeletal transition at the paranodes: the Achilles' heel of myelinated axons. Neuron Glia Biol. 3, 169–178 (2007).
Kirkpatrick, L. L., Witt, A. S., Payne, H. R., Shine, H. D. & Brady, S. T. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons. J. Neurosci. 21, 2288–2297 (2001).
Uschkureit, T., Sporkel, O., Stracke, J., Bussow, H. & Stoffel, W. Early onset of axonal degeneration in double (plp−/−mag−/−) and hypomyelinosis in triple (plp−/−mbp−/−mag−/−) mutant mice. J. Neurosci. 20, 5225–5233 (2000).
Du, Y. & Dreyfus, C. F. Oligodendrocytes as providers of growth factors. J. Neurosci. Res. 68, 647–654 (2002).
Dai, X. et al. The trophic role of oligodendrocytes in the basal forebrain. J. Neurosci. 23, 5846–5853 (2003).
Wilkins, A., Majed, H., Layfield, R., Compston, A. & Chandran, S. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J. Neurosci. 23, 4967–4974 (2003).
McGrail, K. M., Phillips, J. M. & Sweadner, K. J. Immunofluorescent localization of three Na, K-ATPase isozymes in the rat central nervous system: both neurons and glia can express more than one Na, K-ATPase. J. Neurosci. 11, 381–391 (1991).
Young, E. A. et al. Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions. Ann. Neurol. 63, 428–435 (2008).
Tachikawa, M. et al. Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron–glial relationship for brain energy homeostasis. Eur. J. Neurosci. 20, 144–160 (2004).
Brady, S. T. & Lasek, R. J. Nerve-specific enolase and creatine phosphokinase in axonal transport: soluble proteins and the axoplasmic matrix. Cell 23, 515–523 (1981).
Oblinger, M. M., Foe, L. G., Kwiatkowska, D. & Kemp, R. G. Phosphofructokinase in the rat nervous system: regional differences in activity and characteristics of axonal transport. J. Neurosci. Res. 21, 25–34 (1988).
Yuan, A., Mills, R. G., Bamburg, J. R. & Bray, J. J. Cotransport of glyceraldehyde-3-phosphate dehydrogenase and actin in axons of chicken motoneurons. Cell. Mol. Neurobiol. 19, 733–744 (1999).
Galbraith, D. A. & Watts, D. C. Changes in some cytoplasmic enzymes from red cells fractionated into age groups by centrifugation in Ficoll/Triosil gradients. Comparison of normal humans and patients with Duchenne muscular dystrophy. Biochem. J. 191, 63–70 (1980).
Kuehl, L. & Sumsion, E. N. Turnover of several glycolytic enzymes in rat liver. J. Biol. Chem. 245, 6616–6623 (1970).
Medori, R., Autilio-Gambetti, L., Monaco, S. & Gambetti, P. Experimental diabetic neuropathy: impairment of slow transport with changes in axon cross-sectional area. Proc. Natl Acad. Sci. USA 82, 7716–7720 (1985).
Spencer, P. S., Sabri, M. I., Schaumburg, H. H. & Moore, C. L. Does a defect of energy metabolism in the nerve fiber underlie axonal degeneration in polyneuropathies? Ann. Neurol. 5, 501–507 (1979).
Morland, C., Henjum, S., Iversen, E. G., Skrede, K. K. & Hassel, B. Evidence for a higher glycolytic than oxidative metabolic activity in white matter of rat brain. Neurochem. Int. 50, 703–709 (2007).
Brinster, R. L. Lactate dehydrogenase activity in the preimplanted mouse embryo. Biochim. Biophys. Acta 110, 439–441 (1965).
Selak, I., Skaper, S. D. & Varon, S. Pyruvate participation in the low molecular weight trophic activity for central nervous system neurons in glia-conditioned media. J. Neurosci. 5, 23–28 (1985).
Suh, S. W., Aoyama, K., Matsumori, Y., Liu, J. & Swanson, R. A. Pyruvate administered after severe hypoglycemia reduces neuronal death and cognitive impairment. Diabetes 54, 1452–1458 (2005).
Hertz, L., Peng, L. & Dienel, G. A. Energy metabolism in astrocytes: high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J. Cereb. Blood Flow Metab. 27, 219–249 (2007).
Dringen, R., Wiesinger, H. & Hamprecht, B. Uptake of L-lactate by cultured rat brain neurons. Neurosci. Lett. 163, 5–7 (1993).
Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl Acad. Sci. USA 91, 10625–10629 (1994).
Chih, C. P. & Roberts, E. L. Jr. Energy substrates for neurons during neural activity: a critical review of the astrocyte-neuron lactate shuttle hypothesis. J. Cereb. Blood Flow Metab. 23, 1263–1281 (2003).
Allen, N. J., Karadottir, R. & Attwell, D. A preferential role for glycolysis in preventing the anoxic depolarization of rat hippocampal area CA1 pyramidal cells. J. Neurosci. 25, 848–859 (2005).
Magistretti, P. J. Neuron-glia metabolic coupling and plasticity. J. Exp. Biol. 209, 2304–2311 (2006).
Wender, R. et al. Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J. Neurosci. 20, 6804–6810 (2000).
Brown, A. M., Wender, R. & Ransom, B. R. Metabolic substrates other than glucose support axon function in central white matter. J. Neurosci. Res. 66, 839–843 (2001).
Baltan, S. Surviving anoxia: a tale of two white matter tracts. Crit. Rev. Neurobiol. 18, 95–103 (2006).
Butt, A. M., Colquhoun, K. & Berry, M. Confocal imaging of glial cells in the intact rat optic nerve. Glia 10, 315–322 (1994).
Orthmann-Murphy, J. L., Freidin, M., Fischer, E., Scherer, S. S. & Abrams, C. K. Two distinct heterotypic channels mediate gap junction coupling between astrocyte and oligodendrocyte connexins. J. Neurosci. 27, 13949–13957 (2007).
Robinson, S. R., Hampson, E. C., Munro, M. N. & Vaney, D. I. Unidirectional coupling of gap junctions between neuroglia. Science 262, 1072–1074 (1993).
Rash, J. E. et al. Grid-mapped freeze-fracture analysis of gap junctions in gray and white matter of adult rat central nervous system, with evidence for a “panglial syncytium” that is not coupled to neurons. J. Comp. Neurol. 388, 265–292 (1997).
Uhlenberg, B. et al. Mutations in the gene encoding gap junction protein α12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am. J. Hum. Genet. 75, 251–260 (2004).
Orthmann-Murphy, J. L. et al. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 132, 426–438 (2009).
Odermatt, B. et al. Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J. Neurosci. 23, 4549–4559 (2003).
Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S. & Paul, D. L. Connexins are critical for normal myelination in the central nervous system. J. Neurosci. 23, 5963–5973 (2003).
Menichella, D. M. et al. Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity. J. Neurosci. 26, 10984–10991 (2006).
Lutz, S. E. et al. Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation. J. Neurosci. 29, 7743–7752 (2009).
Black, J. A., Foster, R. E. & Waxman, S. G. Rat optic nerve: freeze-fracture studies during development of myelinated axons. Brain Res. 250, 1–20 (1982).
Moffett, J. R., Ross, B., Arun, P., Madhavarao, C. N. & Namboodiri, A. M. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog. Neurobiol. 81, 89–131 (2007).
Jalil, M. A. et al. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. J. Biol. Chem. 280, 31333–31339 (2005).
Tekkok, S. B., Brown, A. M., Westenbroek, R., Pellerin, L. & Ransom, B. R. Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J. Neurosci. Res. 81, 644–652 (2005).
Einheber, S., Bhat, M. A. & Salzer, J. L. Disrupted axo-glial junctions result in accumulation of abnormal mitochondria at nodes of ranvier. Neuron Glia Biol. 2, 165–174 (2006).
Roussarie, J. P., Ruffie, C. & Brahic, M. The role of myelin in Theiler's virus persistence in the central nervous system. PLoS Pathog. 3, e23 (2007).
Ransom, B. R., Butt, A. M. & Black, J. A. Ultrastructural identification of HRP-injected oligodendrocytes in the intact rat optic nerve. Glia 4, 37–45 (1991).
Mastro, A. M. & Keith, A. D. Diffusion in the aqueous compartment. J. Cell Biol. 99, 180s–187s (1984).
Butt, A. M. & Ransom, B. R. Visualization of oligodendrocytes and astrocytes in the intact rat optic nerve by intracellular injection of lucifer yellow and horseradish peroxidase. Glia 2, 470–475 (1989).
Hochachka, P. W. Intracellular convection, homeostasis and metabolic regulation. J. Exp. Biol. 206, 2001–2009 (2003).
Butt, A. M. & Jenkins, H. G. Morphological changes in oligodendrocytes in the intact mouse optic nerve following intravitreal injection of tumour necrosis factor. J. Neuroimmunol. 51, 27–33 (1994).
Werner, H. B. et al. Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J. Neurosci. 27, 7717–7730 (2007).
Li, W. et al. Sirtuin 2, a mammalian homolog of yeast silent information regulator-2 longevity regulator, is an oligodendroglial protein that decelerates cell differentiation through deacetylating a-tubulin. J. Neurosci. 27, 2606–2616 (2007).
Southwood, C. M., Peppi, M., Dryden, S., Tainsky, M. A. & Gow, A. Microtubule deacetylases, SirT2 and HDAC6, in the nervous system. Neurochem. Res. 32, 187–195 (2007).
North, B. J., Marshall, B. L., Borra, M. T., Denu, J. M. & Verdin, E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol. Cell 11, 437–444 (2003).
Bifulco, M., Laezza, C., Stingo, S. & Wolff, J. 2′,3′-Cyclic nucleotide 3′-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin. Proc. Natl Acad. Sci. USA 99, 1807–1812 (2002).
Lee, J., Gravel, M., Zhang, R., Thibault, P. & Braun, P. E. Process outgrowth in oligodendrocytes is mediated by CNP, a novel microtubule assembly myelin protein. J. Cell Biol. 170, 661–673 (2005).
Takenaka, T. et al. Fatty acids as an energy source for the operation of axoplasmic transport. Brain Res. 972, 38–43 (2003).
Kassmann, C. M. & Nave, K. A. Oligodendroglial impact on axonal function and survival – a hypothesis. Curr. Opin. Neurol. 21, 235–241 (2008).
Lasek, R. J., Gainer, H. & Przybylski, R. J. Transfer of newly synthesized proteins from Schwann cells to the squid giant axon. Proc. Natl Acad. Sci. USA 71, 1188–1192 (1974).
Gainer, H., Tasaki, I. & Lasek, R. J. Evidence for the glia-neuron protein transfer hypothesis from intracellular perfusion studies of squid giant axons. J. Cell Biol. 74, 524–530 (1977).
Lasek, R. J., Gainer, H. & Barker, J. L. Cell-to-cell transfer of glial proteins to the squid giant axon. The glia-neuron protein trnasfer hypothesis. J. Cell Biol. 74, 501–523 (1977).
Duncan, A., Ibrahim, M., Berry, M. & Butt, A. M. Transfer of horseradish peroxidase from oligodendrocyte to axon in the myelinating neonatal rat optic nerve: artefact or transcellular exchange? Glia 17, 349–355 (1996).
Court, F. A., Hendriks, W. T., Macgillavry, H. D., Alvarez, J. & van Minnen, J. Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J. Neurosci. 28, 11024–11029 (2008).
Hildebrand, C. & Waxman, S. G. Postnatal differentiation of rat optic nerve fibers: electron microscopic observations on the development of nodes of Ranvier and axoglial relations. J. Comp. Neurol. 224, 25–37 (1984).
Edgar, J. M. et al. Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease. EMBO Mol. Med. 2, 42–50 (2010).
Peters, A., Sethares, C. & Killiany, R. J. Effects of age on the thickness of myelin sheaths in monkey primary visual cortex. J. Comp. Neurol. 435, 241–248 (2001).
McQuarrie, I. G., Brady, S. T. & Lasek, R. J. Retardation in the slow axonal transport of cytoskeletal elements during maturation and aging. Neurobiol. Aging 10, 359–365 (1989).
Verdu, E., Ceballos, D., Vilches, J. J. & Navarro, X. Influence of aging on peripheral nerve function and regeneration. J. Peripher. Nerv. Syst. 5, 191–208 (2000).
Stokin, G. B. & Goldstein, L. S. Axonal transport and Alzheimer's disease. Annu. Rev. Biochem. 75, 607–627 (2006).
Szebenyi, G. et al. Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40, 41–52 (2003).
Williamson, T. L. & Cleveland, D. W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nature Neurosci. 2, 50–56 (1999).
Xu, J. et al. Amyloid-b peptides are cytotoxic to oligodendrocytes. J. Neurosci. 21, RC118 (2001).
Schweigreiter, R., Roots, B. I., Bandtlow, C. E. & Gould, R. M. Understanding myelination through studying its evolution. Int. Rev. Neurobiol. 73, 219–273 (2006).
Chen, S. et al. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nature Neurosci. 6, 1186–1193 (2003).
Salzer, J. L. Polarized domains of myelinated axons. Neuron 40, 297–318 (2003).
I apologize to many colleagues whose work could not be cited owing to space restrictions. I am thankful to D. Attwell, N. Brose, B. Hamprecht, J. Edgar, H. Ehrenreich, C. Kassmann, B. Ransom, J. Salzer, S. Scherer, M. Schnitzer, P. Stys, B. Trapp and H. Werner for helpful discussions and comments on the manuscript. I also thank W. Möbius for electron microscopy images. Work in the Nave laboratory is supported by grants from the BMBF (Leukonet), the DFG (CMPB, SFB/TR43) and the European Union FP6/FP7 (Neuropromise, NGIDD, Leukotreat).
The author declares no competing financial interests.
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Nave, KA. Myelination and the trophic support of long axons. Nat Rev Neurosci 11, 275–283 (2010). https://doi.org/10.1038/nrn2797
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