Here, a role for T-lymphocytes in secondary axonal injury was demonstrated. Similar observations were made in heterozygous myelin protein zero Mpz knockout and homozygous gap junction protein b Gjb1 knockout mice; models of progressive demyelinating forms of the inherited peripheral neuropathies, Charcot Marie Tooth disease CMT; Kobsar et al. Nonetheless, immune cells protect myelin and axons in Mpz deficient mice, a genetic model of a severe dysmyelinating peripheral neuropathy, Dejerine—Sottas syndrome DSS; Berghoff et al.
Hence, the role of the adaptive immune system seems to be dependent on disease-specific mechanisms, probably including myelin integrity and the response of the innate immune system Berghoff et al. All of these diseases were first identified by and later successfully modelled in Plp1 mutant and Plp1 overexpressing mice Nave and Griffiths, ; Gruenenfelder et al. PLP and its isoform DM20 are expressed in oligodendrocytes and located in the compact myelin.
The view that the survival of myelinated CNS axons is linked to the performance of surrounding glial cells initially emerged from studies of Plp1 knockout mouse models Griffiths et al. However, defects in myelin biosynthesis and maintenance do not inevitably lead to axonal degeneration. For example, in the spontaneously occurring Long-Evans shaker les rat and the shiverer mouse, which both lack a functional myelin basic protein Mbp gene Roach et al.
Thus, shiverer elucidates the profound influence the myelinating oligodendrocyte exerts on the axonal cytoskeleton and on radial axonal growth see Cell autonomous and bi-directional signalling regulate axonal and glial dimensions. Of note, the PNS of shiverer mice is fully myelinated Privat et al. Figure 5. Oligodendrocytes support axons. A In the CNS, oligodendrocytes green provide axons with the insulating myelin sheath green: myelinated internodes.
Moreover, oligodendrocytes support axonal integrity and function independent of myelination per se for details see main text. Astrocytes blue not only contact blood vessels but additionally interact with axons and oligodendrocytes and contribute to brain homeostasis.
Oligodendrocyte precursor cells not illustrated are also present in the mature CNS and are the main cellular source for new oligodendrocytes after injury and in remyelination. B Oligodendrocyte dysfunction leads to a perturbed axon-glia interaction which ultimately impairs axonal health. As the myelinic channel system is likely acting as a route by which oligodendrocytes supply metabolites to the myelinated axons, any perturbation of this system could potentially impact axonal integrity, resulting for example in focal axonal swelling and distal axonal degeneration.
De- and dysmyelination are associated with the re distribution of sodium channels along the axolemma, thus maintaining axonal conduction Utzschneider et al. However, the resultant non-saltatory action potential propagation increases energy consumption, and accordingly, increased numbers of mitochondria have been observed in shiverer axons Andrews et al.
Taking advantage of the X-linked nature of the Plp1 gene and female heterozygotes harbouring a mosaic of wild type and PLP-deficient myelin the latter with subtle defects in compaction , we demonstrated that secondary axonal changes, such as organelle-filled focal swellings, are localised to the internodes formed by the PLP-deficient myelin Edgar et al.
This demonstrates that oligodendroglial support of axonal integrity is a very local function. Late onset length-dependent axonal degeneration in this mutant is likely a consequence of these early focal changes and organelle transport stasis Edgar et al. That the axonal changes are secondary to the glial-cell defect was confirmed by cell transplantation experiments Edgar et al. Similarly, Cnp1 knockout mice Lappe-Siefke et al. Thus, abnormal MBP-dependent closures of the myelinic channels likely result in the observed swellings at the inner tongue, that are predicted to perturb axon-glia communication Lappe-Siefke et al.
These and other observations have led us to hypothesise that the myelinic channel system is crucial to the function of the oligodendrocyte in axonal support, likely acting as the route through which the oligodendrocyte supplies metabolites to the myelinated axon and delivers membrane proteins to the adaxonal myelin surface Figure 5.
In the Plp1 transgenic line 72 Readhead et al. This supports our suggestion that axons shielded from nutrients in the extracellular milieu, are susceptible to injury if even minor damage to myelinic channels leaves oligodendrocytes unable to fuel the axon's energy requirements.
Further evidence for a role of oligodendrocytes in axonal support comes from mice lacking the Pex5 gene encoding the peroxisomal biogenesis factor and targeting signal type-I receptor in myelinating glia. In this model, the absence of oligodendroglial peroxisomes does not interfere with myelination but underlies a progressive clinical phenotype caused by subcortical demyelination, inflammation and widespread axonal degeneration Kassmann et al.
Primary oligodendrocyte death also elicits axonal changes. The diphtheria-toxin mediated ablation of oligodendrocytes in mice leads to secondary focal axonal changes and a reduction in axonal densities Ghosh et al. The significant temporal delay between oligodendrocyte cell death and axonal demise can probably be explained by the initial preservation of myelin sheaths, including their content of glycolytic enzymes and metabolite transporters Saab et al.
Axonal changes in this model are independent of the adaptive immune system, as evidenced by crossbreeding to Rag1 deficient mice Pohl et al. Peripheral neuropathies are a heterogeneous group of diseases and result from inflammatory, toxic and metabolic conditions in addition to genetic defects. Evidence for axonal support by Schwann cells emerged from murine mutants and transgenics for the peripheral myelin protein Pmp22 gene encoding the peripheral myelin protein of 22kDA; PMP22 , which model CMT1A.
A Pmp22 point mutation defines the Trembler mouse Suter et al. Schwann cell—axon interactions are perturbed at paranodal glial-axonal junctions in Trembler Robertson et al. Transgenic overexpression of Pmp22 also induces dys- and demyelination and, in this case, a slowly progressive, distally pronounced, axonal loss Sereda et al. HNPP is characterized by focal hypermyelination of peripheral nerves, and the application of mechanical compression induces a conduction block in affected patients as well as in respective animal models Adlkofer et al.
Consistent with this, other CMT forms with increased myelin outfoldings, such as CMT4B, demonstrate a reduced nerve conduction velocity as well as a decreased compound muscle action potential Previtali et al. However, the precise molecular mechanisms of disease progression and functional failure in CMT diseases remain only partially understood, and it is most likely that all human dysmyelinating neuropathies share a defect of Schwann cell-axon communication that is ultimately responsible for axonal conduction blocks, degeneration and a progressive clinical phenotype Nave et al.
Rather, it was the observation that axonal changes occur on axons with relatively Mag and Plp1 knockout mice or completely Cnp1 knockout mice normal-appearing compact myelin that provided evidence that glial cells, independent of myelin, support axonal health Nave, a ; and see Mechanisms of injury: axonal pathology caused by oligodenroglial defects. Mice lacking the myelin-associated glycoprotein Mag gene, assemble CNS and PNS myelin that harbours very minor morphological changes at the inner wrap, but have reduced axon calibre associated with altered neurofilament spacing and phosphorylation in the PNS Yin et al.
A progressive degenerative response including paranodal myelin tomaculi and axonal loss subsequently ensues Yin et al. Just as oligodendrocytes likely provide metabolic support for axons see Energy supply and use , so there is evidence that Schwann cells play a similar role in the PNS. Beirowski et al. LKB1 is a key regulator of energy homeostasis, suggesting axonal degeneration in this model could pertain to axonal energy insufficiency; however the phenotype is complex and its interpretation is not straightforward.
More recently, using mice lacking the nutrient sensing protein O-GlcNAc transferase OGT in Schwann cells, the same group demonstrated that Schwann cell OGT is required for the maintenance of normal myelin and to prevent axonal loss Kim et al.
Recently, using the compound action potential as a readout of ex-vivo sciatic nerve function, Rich and Brown provided evidence that non-myelinated C fibres and myelinated A fibres in the same sciatic nerve preparation, have distinct metabolic profiles. The authors showed that when fructose is supplied as the sole energy source, C fibres can utilise it directly whereas A fibres benefit through receipt of lactate from Schwann cells.
Together, these data are compatible with the hypothesis that myelinating cells provide metabolic support to axons encased in compact myelin, to abrogate the consequences of their being sequestered from extracellular glucose Nave, b. In summary, we have provided an overview of the unique physical and functional properties of myelinated axons, with an emphasis on how these might contribute to the axon's vulnerability to injury in a variety of diseases and traumas.
In some cases, such as SPG10, which is due to a mutation in KIF5A encoding a motor protein of axonal transport , the reason why axons are vulnerable seems evident. However, the particular susceptibility of motor neuron axons in some complex disorders such as familial amyotrophic lateral sclerosis fALS , in which the mutated gene SOD1 ; superoxide dismutase 1 is expressed in all neural cell types, remains an enigma; although multiple mechanisms have been implicated.
In classical axonal and demyelinating GBS, which also fall into this category, antibody-mediated complement activation and downstream calpain-dependent proteolysis is now generally considered the most likely effector of axonal demise Willison et al.
Insight into the effectors of this and other genetically-determined length-dependent axonopathies might come from understanding how axons are injured in the neurotoxic disorders like OPIDN Box 1.
Indeed axonal energy insufficiency might represent a common pathway in multiple neurodegenerative disorders; either due to failure of metabolic support from neighbouring glia; to ischemia as in stroke; or as a consequence of failure of OXPHOS due to nitric oxide and potentially other factors mediated injury to axonal mitochondria summarised in Figure 5B. Thus, actual physical length is not the defining factor.
Recently, we and others demonstrated reduced axonal calibre in mouse models of two complex neuropsychological disorders Rett and Angelman syndromes; Box 5 , which could potentially contribute to symptoms. Thus a variety of axonal changes, from reduced calibre, through mitochondrial dysfunction and focal swelling to transection, can probably all contribute to neurological symptoms in neurodegenerative diseases or injuries with primary or secondary involvement of axons.
Rett and Angelman syndromes comprise part of the spectrum of neurologic disorders previously considered associated with autism Jedele, Both present, after a short period of normal development, with global developmental delay, severe speech and communication deficits, progressive microcephaly, seizures, autistic behavior and a characteristic movement disorder.
Angelman syndrome is due to loss of function of the maternally inherited ubiquitin protein ligase E3A UBE3A allele, while Rett syndrome is due in the majority of cases to loss of function mutation in the X-linked methyl-CpG- binding protein 2 MECP2 gene. Remarkably, clinical features occur in the absence of evident neurodegeneration, and activation of a silenced Mecp2 allele, even with a radically truncated MeCP2 protein, in adult mice reverses neurological and morphological changes, suggesting MeCP2 might be required for maintenance of neuronal function, rather than for normal development Guy et al.
Female mice heterozygous for a Mecp2 null allele develop normally but subsequently exhibit a stiff, uncoordinated gait, tremor, breathing difficulties and hindlimb clasping. Similarly, in a mouse model of Angelman syndrome, reduced axonal diameter and white matter abnormalities underlie impaired brain growth and microcephaly Judson et al.
Similar subtle morphological changes could, in principle, contribute to the neurological signs in Rett and Angelman syndromes. JE and RS wrote the review and provided images. JE planned and edited the review. K-AN was involved in planning, writing and finally edited the manuscript. WM contributed electron micrographs and figure legends. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Adlkofer, K. Hypermyelination and demyelinating peripheral neuropathy in Pmpdeficient mice. Almeida, R. On myelinated axon plasticity and neuronal circuit formation and function.
Andrews, H. Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the shiverer mouse. Arancibia-Carcamo, I. Node of Ranvier length as a potential regulator of myelinated axon conduction speed. Elife 6:e Arthur-Farraj, P. Neuron 75, — Attwell, D. An energy budget for signaling in the grey matter of the brain.
Blood Flow Metab. Avery, M. Cell Biol. Bahey, N. Reduced axonal diameter of peripheral nerve fibers in a mouse model of Rett syndrome. Neuroscience , — Bai, Y. Conduction block in PMP22 deficiency. J Neurosci. Baraban, M. Barros, L. CrossTalk proposal: an important astrocyte-to-neuron lactate shuttle couples neuronal activity to glucose utilisation in the brain.
Bauer, N. Role of the oligodendroglial cytoskeleton in differentiation and myelination. Glia 57, — Bechler, M. CNS myelin sheath lengths are an intrinsic property of oligodendrocytes. Intrinsic and adaptive myelination-A sequential mechanism for smart wiring in the brain.
Beirowski, B. Metabolic regulator LKB1 is crucial for Schwann cell-mediated axon maintenance. Berghoff, M. Neuroprotective effect of the immune system in a mouse model of severe dysmyelinating hereditary neuropathy: enhanced axonal degeneration following disruption of the RAG-1 gene.
Beuche, W. The role of non-resident cells in Wallerian degeneration. Bomont, P. Boullerne, A. The history of myelin. Brady, S. Formation of compact myelin is required for maturation of the axonal cytoskeleton.
Brauckmann, S. The virtue of being too early: Paul A. Life Sci. PubMed Abstract Google Scholar. Bristow, E. The distribution of mitochondrial activity in relation to optic nerve structure. Brown, A. Metabolic substrates other than glucose support axon function in central white matter. Buser, A. The septin cytoskeleton in myelinating glia.
Campbell, G. Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis. FEBS Lett. Cao-Lormeau, V. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 9, — CrossRef Full Text.
Charles, P. Chimelli, L. The spectrum of neuropathological changes associated with congenital Zika virus infection. Acta Neuropathol. Coleman, M. Axon degeneration mechanisms: commonality amid diversity. An kb tandem triplication in the slow Wallerian degeneration Wld s mouse.
Conforti, L. Wallerian degeneration: an emerging axon death pathway linking injury and disease. WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice. Court, F. Morphological evidence for a transport of ribosomes from Schwann cells to regenerating axons.
Glia 59, — Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves. Nature , — Cumberworth, S. Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected.
De Waegh, S. Altered slow axonal transport and regeneration in a myelin-deficient mutant mouse: the trembler as an in vivo model for Schwann cell-axon interactions. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells.
Cell 68, — Di, S. Cell Death Differ. Dirlikov, E. Emerging Infect. Domenech-Estevez, E. Distribution of monocarboxylate transporters in the peripheral nervous system suggests putative roles in lactate shuttling and myelination.
Donaldson, H. On the areas of the axis cylinder and medullary sheath as seen in cross sections of the spinal nerves of vertebrates. Dumenieu, M. The segregated expression of voltage-gated potassium and sodium channels in neuronal membranes: functional implications and regulatory mechanisms. Economo, M.
A platform for brain-wide imaging and reconstruction of individual neurons. Elife 5:e Edgar, J. Johansen-Berg and T. Behrens London: Elsevier , — Google Scholar. Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease. EMBO Mol. Distribution of mitochondria along small-diameter myelinated central nervous system axons.
Early ultrastructural defects of axons and axon-glia junctions in mice lacking expression of Cnp1. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. Emery, B. Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system.
Cold Spring Harb. Engl, E. Non-signalling energy use in the brain. Non-signalling energy use in the developing rat brain. Essuman, K. Neuron 93, — Fernando, R. Fledrich, R. Soluble neuregulin-1 modulates disease pathogenesis in rodent models of Charcot-Marie-Tooth disease 1A. Franklin, R. Neuroprotection and repair in multiple sclerosis. Franssen, E. Fu, M.
Integrated regulation of motor-driven organelle transport by scaffolding proteins. Trends Cell Biol. Fukui, H. Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Funfschilling, U. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity.
Garbern, J. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain , — Gerdts, J. Science , — Neuron 89, — Ghabriel, M. Incisures of schmidt-lanterman. Ghosh, A. Targeted ablation of oligodendrocytes triggers axonal damage.
Gillespie, C. Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron 26, — Gilley, J. Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. Cell Rep. Goebbels, S. A neuronal PI 3,4,5 P3-dependent program of oligodendrocyte precursor recruitment and myelination.
Gomez-Sanchez, J. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves. Griffiths, I. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Groh, J. Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: understanding pathogenesis and chances for treatment.
Glia 65, — Gruenenfelder, F. Axon-glial interaction in the CNS: what we have learned from mouse models of Pelizaeus-Merzbacher disease. Guy, J.
Reversal of neurological defects in a mouse model of Rett syndrome. Hartline, D. Rapid conduction and the evolution of giant axons and myelinated fibers. Hildebrand, C. Myelination and myelin sheath remodelling in normal and pathological PNS nerve fibres. Hinckelmann, M. Self-propelling vesicles define glycolysis as the minimal energy machinery for neuronal transport. Hughes, E. The cell biology of CNS myelination. Hui, S. Glucose feeds the TCA cycle via circulating lactate.
Israeli, E. Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy.
Jang, S. Autophagic myelin destruction by Schwann cells during Wallerian degeneration and segmental demyelination. Glia 64, — Jedele, K.
The overlapping spectrum of rett and angelman syndromes: a clinical review. Judson, M. Decreased axon caliber underlies loss of fiber tract integrity, disproportional reductions in white matter volume, and microcephaly in angelman syndrome model mice. Kang, J. A review of gigaxonin mutations in giant axonal neuropathy GAN and cancer. Kapitein, L. Which way to go? Cytoskeletal organization and polarized transport in neurons.
Cell Neurosci. Kassmann, C. Oligodendroglial impact on axonal function and survival - a hypothesis. Axonal loss and neuroinflammation caused by peroxisome-deficient oligodendrocytes. Kemp, S. X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects. Acta , — doi: Kevenaar, J. The axonal cytoskeleton: from organization to function.
Kim, S. Schwann cell O-GlcNAc glycosylation is required for myelin maintenance and axon integrity. Kirkcaldie, M. The third wave: intermediate filaments in the maturing nervous system. Kirkpatrick, L. Modulation of the axonal microtubule cytoskeleton by myelinating Schwann cells. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons. Kirschner, D. Compact myelin exists in the absence of basic protein in the shiverer mutant mouse.
Klein, D. Myelin and macrophages in the PNS: an intimate relationship in trauma and disease. Brain Res. Kobsar, I. Preserved myelin integrity and reduced axonopathy in GJBdeficient mice lacking the recombination activating gene Koppel, H.
Is there a genuine exuberancy of callosal projections in development? A quantitative electron microscopic study in the cat. Krasnow, A. Regulation of developing myelin sheath elongation by oligodendrocyte calcium transients in vivo. LaMantia, A. Cytological and quantitative characteristics of four cerebral commissures in the rhesus monkey. Lampert, P. A comparative electron microscopic study of reactive, degenerating, regenerating and dystrophic axons.
Neurol 26, — Lappe-Siefke, C. Disruption of the CNP gene uncouples oligodendroglial functions in axonal support and myelination. Lee, S. A culture system to study oligodendrocyte myelination processes using engineered nanofibers. Methods 9, — Lee, Y. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Li, J. Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies.
Lopez-Leal, R. Origin of axonal proteins: is the axon-schwann cell unit a functional syncytium? Cytoskeleton Hoboken 73, — Loreto, A. Genetic dissection of oligodendroglial and neuronal Plp1 function in a novel mouse model of spastic paraplegia type 2. Lundgaard, I. Luse, S. Electron microscopic observations of the central nervous system. Mack, T. Maday, S. Axonal transport: cargo-specific mechanisms of motility and regulation.
Neuron 84, — Mahad, D. Mitochondrial changes within axons in multiple sclerosis. Makhaeva, G. Organophosphorus compound esterase profiles as predictors of therapeutic and toxic effects.
Martini, R. Mice doubly deficient in the genes for MPZ and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. Michailov, G. Axonal Neuregulin-1 regulates myelin sheath thickness. Mikelberg, F. The normal human optic nerve. Axon count and axon diameter distribution. Ophthalmology 96, — Miller, B. A dual leucine kinase-dependent axon self-destruction program promotes Wallerian degeneration. Electron microscopy of myelin: structure preservation by high-pressure freezing.
Monk, K. New insights on Schwann cell development. Glia 63, — Monsma, P. Local regulation of neurofilament transport by myelinating cells. Morell, P. Morfini, G. Axonal transport defects in neurodegenerative diseases. Mosser, J. Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nave, K. Myelination and support of axonal integrity by glia. Myelination and the trophic support of long axons. Myelination of the nervous system: mechanisms and functions.
Cell Dev. Mechanisms of disease: inherited demyelinating neuropathies—from basic to clinical research. Lazzarini, J. Griffin, H. Lassmann, K. Nave, R. Trapp Amsterdam: Elsevier , — Ng, A. The CMT4B disease-causing phosphatases Mtmr2 and Mtmr13 localize to the Schwann cell cytoplasm and endomembrane compartments, where they depend upon each other to achieve wild-type levels of protein expression.
Nicholson, G. A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies. Nijland, P. Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions.
Glia 62, — Nikic, I. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. O'Connor, L. Insertion of a retrotransposon in mbp disrupts mRNA splicing and myelination in a new mutant rat. Oh, Y. Zika virus directly infects peripheral neurons and induces cell death.
Oluich, L. Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination. Osterloh, J. Pan, B. Myelin-associated glycoprotein and complementary axonal ligands, gangliosides, mediate axon stability in the CNS and PNS: neuropathology and behavioral deficits in single- and double-null mice.
Papandreou, M. The functional architecture of axonal actin. Patzig, J. Elife Pereira, J. Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci. Perge, J. How the optic nerve allocates space, energy capacity, and information. Why do axons differ in caliber? Perry, V. Macrophages and microglia in the nervous system. The macrophage response to central and peripheral nerve injury.
A possible role for macrophages in regeneration. Peters, A. The node of Ranvier in the central nervous system. Microtubules and filaments in the axons and astrocytes of early postnatal rat optic nerves.
Pohl, H. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. Poitelon, Y. Previtali, S. Expert Rev. This mode of travel by the action potential is called "saltatory conduction" and allows for rapid impulse propagation Figure 1A.
Following demyelination, a demyelinated axon has two possible fates. The normal response to demyelination, at least in most experimental models, is spontaneous remyelination involving the generation of new oligodendrocytes. In some circumstances, remyelination fails, leaving the axons and even the entire neuron vulnerable to degeneration.
Remyelination in the CNS: from biology to therapy. Nature Reviews Neuroscience 9, — All rights reserved. Figure Detail What happens if myelin is damaged? The importance of myelin is underscored by the presence of various diseases in which the primary problem is defective myelination. Demyelination is the condition in which preexisting myelin sheaths are damaged and subsequently lost, and it is one of the leading causes of neurological disease Figure 2. Primary demyelination can be induced by several mechanisms, including inflammatory or metabolic causes.
Myelin defects also occur by genetic abnormalities that affect glial cells. Regardless of its cause, myelin loss causes remarkable nerve dysfunction because nerve conduction can be slowed or blocked, resulting in the damaged information networks between the brain and the body or within the brain itself Figure 3.
Following demyelination, the naked axon can be re-covered by new myelin. This process is called remyelination and is associated with functional recovery Franklin and ffrench-Constant The myelin sheaths generated during remyelination are typically thinner and shorter than those generated during developmental myelination.
In some circumstances, however, remyelination fails, leaving axons and even the entire neuron vulnerable to degeneration. Thus, patients with demyelinating diseases suffer from various neurological symptoms. The representative demyelinating disease , and perhaps the most well known, is multiple sclerosis MS. This autoimmune neurological disorder is caused by the spreading of demyelinating CNS lesions in the entire brain and over time Siffrin et al.
Patients with MS develop various symptoms, including visual loss, cognitive dysfunction, motor weakness, and pain. Approximately 80 percent of patients experience relapse and remitting episodes of neurologic deficits in the early phase of the disease relapse-remitting MS. There are no clinical deteriorations between two episodes. Approximately ten years after disease onset, about one-half of MS patients suffer from progressive neurological deterioration secondary progressive MS.
About 10—15 percent of patients never experience relapsing-remitting episodes; their neurological status deteriorates continuously without any improvement primary progressive MS. Importantly, the loss of axons and their neurons is a major factor determining long-term disability in patients, although the primary cause of the disease is demyelination.
Several immunodulative therapies are in use to prevent new attacks; however, there is no known cure for MS. Figure 3 Despite the severe outcome and considerable effect of demyelinating diseases on patients' lives and society, little is known about the mechanism by which myelin is disrupted, how axons degenerate after demyelination, or how remyelination can be facilitated.
To establish new treatments for demyelinating diseases, a better understanding of myelin biology and pathology is absolutely required. How do we structure a research effort to elucidate the mechanisms involved in developmental myelination and demyelinating diseases? We need to develop useful models to test drugs or to modify molecular expression in glial cells. One strong strategy is to use a culture system. Coculture of dorsal root ganglion neurons and Schwann cells can promote efficient myelin formation in vitro Figure 1E.
Researchers can modify the molecular expression in Schwann cells, neurons, or both by various methods, including drugs, enzymes, and introducing genes , and can observe the consequences in the culture dish. Modeling demyelinating disease in laboratory animals is commonly accomplished by treatment with toxins injurious to glial cells such as lysolecithin or cuprizone. Autoimmune diseases such as MS or autoimmune neuropathies can be reproduced by sensitizing animals with myelin proteins or lipids Figure 3.
Some mutant animals with defects in myelin proteins and lipids have been discovered or generated, providing useful disease models for hereditary demyelinating disorders. Further research is required to understand myelin biology and pathology in detail and to establish new treatment strategies for demyelinating neurological disorders.
Myelin can greatly increase the speed of electrical impulses in neurons because it insulates the axon and assembles voltage-gated sodium channel clusters at discrete nodes along its length. Myelin damage causes several neurological diseases, such as multiple sclerosis. Future studies for myelin biology and pathology will provide important clues for establishing new treatments for demyelinating diseases.
Brinkmann, B. Neuron 59 , — Franklin, R. Remyelination in the CNS: From biology to therapy. Nature Reviews Neuroscience 9 , — Nave, K. Axonal regulation of myelination by neuregulin 1. Current Opinion in Neurobiology 16 , — Poliak, S.
The local differentiation of myelinated axons at nodes of Ranvier. Nature Reviews Neuroscience 4 , — Sherman, D. Mechanisms of axon ensheathment and myelin growth.
Nature Reviews Neuroscience 6 , — Siffrin, V. Multiple sclerosis — candidate mechanisms underlying CNS atrophy. Trends in Neurosciences 33 , — Susuki, K. Molecular mechanisms of node of Ranvier formation. Current Opinion in Cell Biology 20 , — Cell Signaling. Ion Channel. Cell Adhesion and Cell Communication. Aging and Cell Division.
Endosomes in Plants. Ephs, Ephrins, and Bidirectional Signaling. Ion Channels and Excitable Cells. Signal Transduction by Adhesion Receptors. Citation: Susuki, K. Nature Education 3 9 How does our nervous system operate so quickly and efficiently? The answer lies in a membranous structure called myelin.
Aa Aa Aa. Information Transmission in the Body. Figure 1. Figure Detail. Axonal Signaling Regulates Myelination. Figure 2: The fate of demyelinated axons. The case in the CNS is illustrated. Research in Myelin Biology and Pathology. Figure 3.
References and Recommended Reading Brinkmann, B. Waxman, S. The Axon: Structure, Function and Pathophysiology. New York: Oxford University Press, Article History Close. Share Cancel. Revoke Cancel. Keywords Keywords for this Article. Save Cancel.
0コメント