Neurochemical Mechanisms in Disease P56 docx

Endogenous Antinociceptive Ligands 535 Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, Morenilla-Palao C, Stirling C, Fitzgerald M, McMahon SB (2006) Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci 31:539–548 Zhao M, Wang JY, Jia H, Tang JS (2007) Roles of different subtypes of opioid receptors in mediat- ing the ventrolateral orbital cortex opioid-induced inhibition of mirror-neuropathic pain in the rat. Neuroscience 144:1486–1494 Zheng L, Li XC (1995) Effect of intracerebroventricular injection of somatostatin or gaba on pain threshold and contents of GABA or somatostatin in rat-brain. Acta Pharmacol Sin 16:329–332 Zheng W, Xie W, Zhang J, Strong JA, Wang L, Yu L, Xu M, Lu L (2003) Function of gamma-aminobutyric acid receptor/channel rho 1 subunits in spinal cord. J Biol Chem 278: 48321–48329 Zhou XF, Deng YS, Xian CJ, Zhong JH (2000) Neurotrophins from dorsal root ganglia trigger allodynia after spinal nerve injury in rats. Eur J Neurosci 12:100–105 Zhuo M, Gebhart GF (1990) Spinal cholinergic and monoaminergic receptors mediate descending inhibition from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat. Brain Res 535:67–78 Zhuo M, Gebhart GF (1991) Tonic cholinergic inhibition of spinal mechanical transmission. Pain 46:211–222 Zollner C, Shaqura MA, Bopaiah CP, Mousa S, Stein C, Schafer M (2003) Painful inflammation- induced increase in mu-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol 64:202–210 Zubrzycka M, Fichna J, Janecka A (2005) Inhibition of trigemino-hypoglossal reflex in rats by oxytocin is mediated by mu and kappa opioid receptors. Brain Res 1035:67–72 Zubrzycka M, Janecka A (2007) Effect of tooth pulp stimulation on oxytocin and vasopressin release into the cerebrospinal fluid and fluid perfusing the cerebral ventricles in rats. Endocr Regul 41:149–154 Zubrzycka M, Janecka A (2008) Interactions of galanin with endomorphin-2, vasopressin and oxytocin in nociceptive modulation of the trigemino-hypoglossal reflex in rats. Physiol Res 57:769–776 Biology of Demyelinating Diseases Danielle Pham-Dinh and Nicole Baumann Abstract Demyelinating diseases are those in which myelin is the primary target of damage on the basis of neuroradiological, neuropatholgical, neurochemical, and genetic studies. This review describes the morphological aspects of the myelin sheath which is the most abundant membrane structure in the vertebrate nervous system. It is made of oligodendrocytes in the CNS and Schwann cells in the PNS. It comprises four distinct regions: the node of Ranvier which contains voltage-gated Na+ channels, paranodal loops which are major sites of myelin-axon adhesion, the juxtaparanode, and the internode which is the part of the axon which is ensheathed by a segment of myelin. Demyelination is segmental in the peripheral nervous system and focal in the central nervous system. Myelin is necessary for nerve conduction velocity. Dys- and demyelination can involve specific constituents of the CNS and the PNS both for genetic (leukodystrophies) or acquired diseases. Numerous components are different and differently involved in CNS and PNS myelin, both among proteins and lipids (sphingolipids). Outside of the abnormalities of specific myelin components leading to genetic diseases, experimental models of demyelination (experimental autoimmune encephalomyelitis, cuprizone intoxica- tion, lysolecithin-induced demyelination, and ethidium bromide treatment are also described). During myelin repair, a thinner myelin sheath is produced with shorter internodes and efficient nerve conduction is produced. Dysfunction of astrocytes may be involved in some genetic diseases of myelin. There are many growth factors and transcription factors involved in the process of myelination and demyelination among which eukaryotic initiation factor 2B (elf2B) leading to vanishing white matter disease (CACH). The role of hormones and sexual dimorphism of oligodendrocytes and myelin anre also described. New areas of research are being developed showing the involvement of myelin deficiency in psychiatric diseases and cognition. N. Baumann (B) Laboratoire de Neurochimie, Hôpital de la Salpêtrière, F-75013 Paris, France; Université Paris 6, F-75000 Paris, France e-mail: nicole.baumann@upmc.fr 537 J.P. Blass (ed.), Neurochemical Mechanisms in Disease, Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_16, C  Springer Science+Business Media, LLC 2011 538 D. Pham-Dinh and N. Baumann Keywords Myelin proteins · Myelin lipids · Demyelination · Leukodystrophies · Multiple sclerosis Contents 1 Introduction 538 2 Morphological Aspects 540 2.1 Myelin Structure in the Central and Peripheral Nervous System 540 2.2 Node of Ranvier 541 2.3 Paranode 541 2.4 Myelination 541 2.5 Demyelination 542 3 Dys- and Demyelination in Relation to Specific Constituents 547 3.1 CNS Myelin Proteins 547 3.2 PNS Myelin Proteins 555 3.3 Proteins and Specific Lipids of the Node of Ranvier and the Paranodal and Juxtaparanodal Areas 557 3.4 Dys- or Demyelination in the CNS and/or the PNS Related to Myelin Lipid Compounds 559 4 Other Glial Cell Types and Factors Involved in Myelination and Demyelination in the CNS 563 4.1 Astrocytes and Mutations in GFAP 563 4.2 Oligodendrocyte Precursors 564 4.3 Biochemical Factors 565 5 Conclusion 570 References 571 1 Introduction Different myelin disorders affect several million people in the world, whereby myelin is the primary target of damage on the basis of neuroradiological, neuropathological, neurochemical, and genetic studies. There are primary genetic diseases in which the targets are specific components of myelin or myelin control. Interestingly, even in the latter which are leukodystrophies in CNS or peripheral neuropathies in PNS, there are wide variations according to each individual, and in most cases there are no clear relations between genotype and phenotype. This indicates that the factors involved may be multiple. Myelin disorders also include acquired diseases such as multiple sclerosis (MS) in the central nervous system (CNS), and Guillain–Barré syndrome (already recognized as having multiple causes) in the peripheral nervous system (PNS), although genetic susceptibility may be involved. The myelin sheath is one of the most abundant membrane structures in the vertebrate nervous system. It is produced by two types of glial cells, oligodendrocytes in the CNS and Schwann cells in the PNS. The myelin sheath is formed by the Biology of Demyelinating Diseases 539 spiral wrapping of glial plasma membrane extensions around the axon, followed by the extrusion of cytoplasm and the compaction of the stacked myelin bilayers (Simons and Trajkovic, 2006). The myelination process is dependent on neuronal activity (Demerens et al., 1996; Lubetzki and Stankoff, 2000) and has recently been found to be relayed in the CNS by the nonmyelinating cells, the astrocytes (Ishibashi et al., 2006; Spiegel and Peles, 2006). Myelin structure and composition differ somehow in both CNS and PNS (Baumann and Pham-Dinh, 2001), but the function of myelin is the same: to allow r apid nerve conduction through nerve fibers, especially those integrating the motor and sensory functions in ver- tebrates (Waxman and Bangalore, 2003). Moreover, in mammals, and especially in higher primates in which myelination is a long-lasting process (Yakovlev and Lecours, 1966), particularly in association areas, it is now clear that myelin is involved in cognitive functions such as language (Aslin and Schlaggar, 2006; Pujol et al., 2006) and behavior (Beckman, 2004; Seldon, 2007); recently it has been shown that alteration of CNS myelin may be involved in some psychiatric diseases (Stewart and Davis, 2004; Kubicki et al., 2005; Regenold et al., 2007) and dementia (Filley, 1998). The symptoms characteristic of myelin disorders may be caused by abnormal formation of myelin (i.e., dysmyelination) or damage to myelin (i.e., demyelination; Baumann and Pham-Dinh, 2001). In fact, it may be sometimes difficult to separate the two aspects, as some of those diseases, even the genetic ones linked to alterations of myelin constituents, may appear only at an adult age. Thus it is necessary to consider both aspects. Furthermore, conduction abnormalities are not due only to changes in the electrical properties related to myelin loss, but also to modifications in electrogenic properties related to alterations of the molecular organization within the axonal membrane. It is not always easy to understand what phenomenon is at the origin of the disease. Nevertheless, we focus here on dys- and demyelinating diseases in which myelin modifications appear to be the primary events. This includes diseases involving the cells that build and preserve myelin such as oligodendrocytes in the CNS and Schwann cells in the PNS, and alterations of neuron–glia interactions (involving astrocytes in the CNS and possibly microglia). In this review, we do not speak about secondary demyelinations in which the cause is related to abnormalities of cerebral vasculature such as vascular dementia, stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), or Fabry’s disease, or abnormalities of mitochondrial functions such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Also, clinically significant white matter changes can be seen on MRI (magnetic resonance imaging) in some genetic and inflammatory diseases in which the most prominent neuropathological abnormalities are in the grey matter. For instance, tumors with the potential to infiltrate the white matter may also cause dramatic changes in white matter that are evident in MRI. We do not cite here many references that have been mentioned extensively in a review on the biology of myelination in the central nervous system by Baumann and Pham-Dinh (2001) especially because this review is freely available on the Internet. 540 D. Pham-Dinh and N. Baumann Extensive reviews on different aspects of myelin biology and disorders are available in the book by R.A. Lazzarini (Lazzarini, 2004). Before determining the chemical factors involved in myelin disorders, it is useful to first recall the morphological particularities of myelin and the Ranvier node, in CNS and PNS, as these are the major targets of demyelination. 2 Morphological Aspects 2.1 Myelin Structure in the Central and Peripheral Nervous System Myelin is a spiral structure made up of extensions of the plasma membrane from the myelinating glial cells, namely the oligodendrocytes in the CNS and the Schwann cells in the PNS. These cells send out sail-like extensions of their cytoplasmic membrane, each of which forms a segment of sheathing around an axon, which then constitutes the myelin sheath. The s tructure of myelinated axons is similar in both the CNS and PNS. There are four distinct regions: the node of Ranvier, the paranode, the juxtaparanode, and the internode. The internode is the part of the axon that is ensheathed by a segment of myelin; it ends at both sides in the juxtaparanode; then paranodal loops border the node of Ranvier, a portion of the axon that is exposed to the extracellular milieu. Several structural features characterize myelin in electron microscopy: a periodic structure, with alternating concentric electron-dense and light layers. The major dense line (dark layer) forms as the cytoplasmic surfaces of the expanding myelinating processes of the oligodendrocyte or the Schwann cell are brought into close apposition; the fused two outer leaflets (extracellular apposition) form the intraperiodic lines or minor dense lines. The periodicity of compact CNS and PNS myelin differs only slightly, however, CNS and PNS myelin can be easily distinguished by the presence of a basal lamina around PNS but not CNS myelin. Also, the endoneural or extracellular space of peripheral nerves is particularly abundant. PNS and CNS myelin internodes are separated from the axon by a 12–14-nm periaxonal space. The regularly spaced unmyelinated gaps that constitute the node of Ranvier are critical to the proper function of CNS and PNS myelin. Both the structure and the molecular organization of the nodal region are dependent on the formation of the appropriate axo–glial interactions. These interactions establish the spacing of adjacent myelin segments (internodes) and ultimately determine the position and length of the nodal gaps. Compact myelin constitutes the internodes whereas juxtaparanode and paranodal loops are mostly formed by noncompact myelin. The juxtaparanode is just under the compact myelin sheath beyond the innermost paranodal junction and may therefore be considered as a specialized portion of the internode (Peles and Salzer, 2000). Biology of Demyelinating Diseases 541 2.2 Node of Ranvier The nodal axolemma is a functional part of myelin formation as it contains voltage- gated Na+ channels and thereby is directly responsible for saltatory conduction. This architecture is accompanied by a selective disposition of different types of ion exchangers and channels that allow the saltatory conduction of nervous influx and are responsible for its high velocity, without increasing axonal diameter. A high density of voltage-gated Na+ channels is found at the node of Ranvier, whereas K+ channels are found at the juxtaparanodal loops. The node of Ranvier, paranodal junctions and the adjacent juxtaparanodal regions each contain distinct protein complexes. Each of these membrane domains contains a specific set of cell adhesion molecules that are stabilized and retained through interactions with cytoskeletal and scaffolding proteins. These in turn recruit and stabilize the appropriate channels (Coman et al., 2005; Simons and Trajkovic, 2006). Although PNS and CNS nodes can appear similar by transmission electronic microscopy (TEM), each is surrounded by distinctly different immediate environ- ments. The nodal axolemma is surrounded by Schwann cell microvilli in the PNS and by glial cell processes in the CNS. The microvilli extending from the outer border of the adjacent myelin internodes are best visualized in cross-sections. The Schwann cell basal lamina is continuous across the node but does not surround individual microvilli. The glial cell processes surrounding CNS nodes originate from a recently described cell population: the NG2 cells (Butt et al., 2002). These CNS glial processes do not, however, closely adhere to all regions of the nodal axolemma. 2.3 Paranode The cytoplasmic channels or paranodal loops at the lateral end of the internode are a major site of myelin–axon adhesion. The membrane of the inner or adaxonal surface of the myelin sheath is in direct contact with the axons. Their cytoplasmic channels may transmit axonal signals that regulate myelin formation and help determine the length and thickness of the myelin internode. These channels contain microtubules and other cytoskeletal components for transport and stability and mitochondria for energy. Also, in some areas, they contain smooth endoplasmic reticulum and free polysomes for the synthesis of local membrane components. In addition, membranes of noncompact myelin serve special functions that are reflected by unique molecular composition. 2.4 Myelination As mentioned previously, myelination is carried out by highly specialized glial cells, oligodendrocytes in the CNS and Schwann cells in the PNS. These cells differentiate from precursor cells of different origin during development: the neural crest for Schwann cells, and neural tube for oligodendrocytes. Myelin characteristics differ morphologically in the CNS and in the PNS, and differ also inside the CNS. Thus 542 D. Pham-Dinh and N. Baumann regulation of myelination and most probably demyelination takes place according to different criteria. Oligodendrocytes differ from Schwann cells in that they have the ability to form multiple myelin internodes and do so by each extending multiple processes to form an internode on several partner axons at a distance from the cell body (Baumann and Pham-Dinh, 2001). In the PNS, a single Schwann cell synthesizes only one internode. Myelin sheath thickness (Graham and Lantos, 1997), internodal length, and width of nodes show a constant relationship to axonal diameter in normal tissue. In the CNS, nodal length is related to the diameter of the axon and can vary from less than 1 μm in the small fibers of the optic nerve to more than 5 μmin the large fibers of the spinal cord. In the CNS the majority of axons over 0.6 μmin diameter are surrounded by a myelin sheath. In the PNS myelin internodes are 0.5 μm long. CNS internodes surrounding small diameter axons are shorter and thinner than those surrounding large diameter axons. The number of internodes synthesized by one oligodendrocyte depends on the location in the CNS, for example, up to 50 in the optic nerve where axons are of small diameter, but much less in the spinal cord comprising large-diameter axons. In both CNS and PNS, an external layer of noncompact myelin still containing cytoplasm lines the exterior of the internodes. In addition to this structure, internodes of PNS myelin comprise specific channels, the Schmidt–Lanterman incisures that connect outer and inner regions of the internode. This structure is not found in CNS internode myelin. In the CNS, there is also a radial component formed by points of focal adhesion between sheaths which helps maintain CNS myelin integrity. Interestingly, different areas of the CNS are myelinated at different times (Yakovlev and Lecours, 1966). In the spinal cord, there is a caudo–rostral progres- sion but even within a tract system, all the axons are not myelinated simultaneously. The process of myelination represents one of the clearest examples of cell–cell cooperation. Neither axons nor myelin-forming cells can functionally differentiate to completion without each other (Trapp et al., 2004), although oligodendrocytes produce significant amounts of myelin-like membrane in neuron-free culture. The Schwann cells that myelinate PNS behave differently. Once they reach their final destination, each Schwann cell surrounds several small-diameter axons in a polyaxonal pocket. As axons mature, the Schwann cell segregates a single axon from the polyaxonal pocket. Thus Schwann cells in peripheral nerves have two major phenotypes: those that ensheath multiple axons (unmyelinated fibers) and those that myelinate single axons. The production of a basal lamina is a prerequisite for myelination. Our knowledge of the molecular composition of myelin internodes is substan- tial, however, we know little about the molecular mechanism responsible for spiral wrapping of myelin membranes or for axon–myelin forming cell communication. 2.5 Demyelination One of the particulars of demyelination in the CNS and the PNS is the fact that they are focal for the CNS and segmental for the PNS. Biology of Demyelinating Diseases 543 2.5.1 Primary Demyelination and Hypomyelination in the CNS. Prospects for Remyelination in MS and leukodystrophies One must distinguish active and chronic demyelination. In active primary demyelination (Graham and Lantos, 1997), the pathology is often focal and the removal of myelin sheaths is accompanied by a florid infiltration of macrophages that quickly accumulate myelin debris and become transformed in fat-filled macrophages; there is also a marked astrocytic hypertrophy and hyperplasia. Areas of chronic demyelination appear as areas of astrocytosis devoid of myelin in which demyelinated axons can be shown to be in continuity with normally myelinated axons in the surrounding white matter. The identification of remyelination, partial demyelination, and hypomyelination can prove difficult. All these changes appear as axons enveloped by myelin sheaths too t hin for the axons they surround. Too thin myelin sheaths and/or too short internodes indicate hypomyelination if present throughout the white matter and remyelination if found in otherwise normal white matter in the adult. In partial demyelination, the dimensions of myelin sheaths are irregu- larly reduced; internodes of normal length may be too thin for the diameter of the axon they enclose, or short, thinly myelinated axons are interposed between normal size internodes. In fact this formulation is too schematic, as some genetic demyelinating diseases which start at adolescence and/or adulthood show normal areas of myelination, and focal and diffuse demyelination, in relation to areas that are myelinated at later stages. In most instances, selective loss of whole internodes of myelin results from the death of the oligodendrocytes. The paranodal junctions attaching the myelin sheath to the axonal surface may represent privileged targets at the onset of demyelination (Coman et al., 2005). Leukodystrophies are specific diseases affecting the white matter of the CNS (brain, optic nerve, and spinal cord); they are genetic diseases affecting different components of the myelinating glial cells, the oligodendrocytes, or of myelin itself. Structure proteins, growth factors, or transcription factors may be involved. Recently, the nonmyelinating glial cells of the CNS, the astrocytes, have been shown to be the direct target of a myelin disease. Numerous animal models have been engi- neered to mimic and study human diseases; they include overexpressing transgenic mice or rats, knock-out mice in which a gene has been invalidated, and knock-in ani- mals bearing a mutation pathogenic in a human gene. All these models have been invaluable tools to study genetic diseases of myelin. Multiple sclerosis (MS) is probably not a monogenic disease, and may be caused by a deregulation of the immune system, with more or less specificity for several myelin constituents, proteins or lipids. In general, multiple sclerosis begins in early adulthood and has two phases. There is a relapsing-remitting phase which often lasts 5–10 years; 30% of individuals enter a secondary chronic progressive state. Occasionally, clinical disability begins with this progressive phase in which case the disease is called “primary progressive MS” (Steinman, 2001). Evidence indicates that the earlier phase of the disease, characterized by distinct attacks followed by remission may be mediated by an autoimmune inflammatory reaction. The sub- sequent chronic phase of the disease is caused by degeneration of both the myelin 544 D. Pham-Dinh and N. Baumann sheath and the underlying axon. Axon loss in the spinal cord and spinal cord atro- phy correlate most strongly with the inability to walk and with paralysis. With the discovery of early and widespread loss of axons in the disease, new emphasis has been put on the role of axon–oligodendrocyte interactions in MS (Williams et al., 2007a). Myelin repair and neuroprotection represent major goals in strategies for MS and represent very active fields of research therapy (Lubetzki et al., 2005). Glial scars composed of astrocytes may prevent remyelinating cells from gaining access to demyelinated axons. However astrocytes also produce a wide range of signaling molecules that support recruitment, and so it is not clear whether astrocytes are friends or foes (Williams et al., 2007a). The signaling environment of the plaque is crucial for the success of remyelination, and it appears t hat inflammation may play a beneficial role (Bradl and Hohfeld, 2003). 2.5.2 Primary Demyelination and Hypomyelination in the PNS: Charcot-Marie Tooth Diseases (CMT) Primary segmental demyelination is a disturbance of Schwann cell function or of myelin itself. The initial changes are observed at the nodes of Ranvier. There is myelin retraction and widening of the node. There is paranodal demyelination or the process extends to the whole of the internode leaving a denuded axon. The nerve is invaded by macrophages that engulf the myelin debris. There can be a primary demyelination related to abnormality of Schwann cell function. Demyelination may also be related to an axonal disease. Repeated demyelination and remyelination is encountered in a wide range of disorders. An excess of Schwann cells after demyelination creates an onion bulb formation in chronic neuropathies. Possibly the presence of unmyelinated axons is required for supernumerary Schwann cells to persist (Graham and Lantos, 1997). CMT diseases are the most frequent hereditary sensory-motor neuropathies. They are distinguished from other types of genetic neuropathies, either purely motor, mainly distal and dysautonomous neuropathies which mainly alter sensory and sympathetic fibers of the peripheral nerves. We only deal here with CMT diseases and among the many genetic causes, those that give rise to primary demyelinating diseases of the peripheral nervous system (PNS). The accepted classification of CMT relies on the type of genetic transmission as well as on the electroneuromyographic (ENMG) criteria. Measurement of nerve conduction velocity allows a distinction between demyelinating and axonal forms, because conduction velocity is decreased when there is demyelination. The classification may be discussed in relation to the degree of nerve conduction velocity reduction. We adopt the classification of Dubourg (2004). There are truly demyelinating f orms with a nerve conduction velocity for the median nerve of 30 m/s, axonal forms with a nerve conduction velocity for the median nerve above 40 m/s and intermediary forms. The molecular analysis confirms the data of the EMG with a very good genotype/phenotype correlation but the penetrance can be variable in the same families. The autosomal dominant form is the most frequent, classically called CMT1, with several subtypes related to the mutations of different proteins. . transmission. Pain 46:211–222 Zollner C, Shaqura MA, Bopaiah CP, Mousa S, Stein C, Schafer M (2003) Painful in ammation- induced increase in mu-opioid receptor binding and G-protein coupling in primary. at the origin of the disease. Nevertheless, we focus here on dys- and demyelinating diseases in which myelin modifications appear to be the primary events. This includes diseases involving the cells. myelin or myelin control. Interestingly, even in the latter which are leukodystrophies in CNS or peripheral neuropathies in PNS, there are wide variations according to each individual, and in

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