9
Biogenesis and Significance of Central Nervous
System Myelin
Istvan Pirko, M.D. 1
1 Department of Neurology, Mayo Clinic, Rochester, Minnesota
Semin Neurol 2012;32:9–14.
Abstract
Keywords
► myelin
► structure of myelin
► function of myelin
Address for correspondence and reprint requests Istvan Pirko, M.D.,
Associate Professor, Department of Neurology, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905 (e-mail: [email protected]).
The central nervous system is composed of neurons and glia cells. Although neurons
have long been considered the functionally important cells, an ever-expanding body of
research has revealed many critical functions of neuroglia. Among these, the myelin
sheath elaborated by oligodendrocytes acts as a dynamic partner to the axons it
enwraps and can no longer be considered as an inert membrane. In addition to its best
known roles of providing insulation and optimizing conduction velocity, myelination
modulates the maturation, survival, and regenerative capacity of axons through trophic
support and signaling molecules. Myelin is produced through a complex process
involving cell differentiation, biosynthesis of specialized lipids and proteins, interaction
with environmental signals, and coordinated changes in cell morphology. Understanding the pathophysiology of primary myelin disorders, and the challenges faced in
treating them, is facilitated through understanding of the structure, function, and
generation/regeneration of myelin.
Central nervous system (CNS) research, in terms of cellular
structure and function, historically focused on neurons at the
expense of glia cells. Neurons were considered the functionally important cells, whereas glia cells were felt to be little
more than scaffolding. Fortunately, the past few decades have
witnessed an expanding body of knowledge in regard to glial
function, but our understanding still lags behind that of
neurons.
Within the CNS, three primary glial cell types are recognized: microglia, astrocytes, and oligodendrocytes. Microglia
cells function as resident immune cells and are capable of
phagocytosis. Astrocytes have numerous processes that contact capillaries, neurons, other glia cells, the lining of cerebral
ventricles, and the extracellular environment. Through these
processes they form the blood–brain barrier and glia limitans,
maintain ion and osmotic homeostasis, uptake neurotransmitters, modulate synaptic activity, and communicate with
surrounding cells. Oligodendrocytes form a specialized membrane process, the myelin sheath, which surrounds and
insulates axons. Classically thought of as an electrical insulator only, myelin and oligodendrocytes serve multiple functions that are still being elucidated. Here we will describe the
Issue Theme Inherited
Leukoencephalopathies; Guest Editor,
Deborah L. Renaud, M.D.
architecture and composition of myelin and its relationship to
physiology and pathophysiology.
Myelin Architecture
Myelin is a multilayered membrane system that enwraps
axons with a characteristic periodic structure. In the CNS, this
membrane system is produced by and extends from oligodendrocytes. Unlike Schwann cells in the peripheral nervous
system, oligodendrocytes have the ability to form multiple
segments of myelin, both along a single axon and across
multiple axons. Myelin segments (internodes) along individual myelinated axons are separated by short stretches of bare
axolemma (nodes of Ranvier). Morphologically, the myelin
internode consists of compact myelin, which comprises the
majority of the internode, and noncompact myelin, which
primarily frames the edges of the internode (►Fig. 1).
Compact myelin is a spiraled cellular sheet composed of two
plasma membranes, which forms a lamellar structure of
alternating electron-dense and electron-light layers
(►Fig. 2). The electron-dense layers (major dense lines) represent the fused cytoplasmic membrane leaflets, whereas the
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DOI http://dx.doi.org/
10.1055/s-0032-1306381.
ISSN 0271-8235.
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M. Mateo Paz Soldán, M.D., Ph.D. 1
Biogenesis and Significance of Central Nervous System Myelin
Figure 1 Schematic view of myelin. Multiple processes extend from
the oligodendrocyte cell body to form cellular sheets composed of two
plasma membranes. The membrane sheets enwrap axons to form
myelin internodes. Viewed in its unwrapped state, the myelin sheet is
composed primarily of compacted plasma membranes. Noncompacted cytoplasmic channels are present at its borders, forming the
abaxonal, paranodal, and periaxonal loops. The cytoplasmic loops are
continuous with each other and with the cell body.
electron-light layers (intraperiod lines) represent the tightly
apposed outer membrane leaflets. As suggested by the nature
of the major dense lines, cytoplasm is largely excluded from
compact myelin. Extracellular space, contrastingly, is present
at the intraperiod lines. Radial components are another ultrastructural feature of compact CNS myelin. These are composed
of lines of junctional complexes registered both longitudinally
and transversely, across the length of the internode and
thickness of the myelin sheath, respectively.
Noncompact myelin is present at the edges of the myelin
cellular sheet, as well as occasional longitudinal incisures
within the compacted myelin membranes (►Fig. 1). Membrane loops at the inner- (periaxonal) and outermost (abaxonal) edges of the sheet form channel-like tubes that
longitudinally traverse the entire internode, whereas longitudinal incisures only partially traverse the internode. Membrane loops at the lateral (paranodal) edges of the sheet form
analogous channel-like tubes that provide cytoplasmic continuity between the abaxonal loop, longitudinal incisures,
and periaxonal loop. Each of these membrane loops may
contain smooth endoplasmic reticulum and vesicles for metabolic processes, cytoskeletal elements for transport and
stability, mitochondria for energy, and together enable communication between the oligodendrocyte soma and the
myelin lamellae.
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Examined longitudinally, noncompact myelin along the
lateral margins of the internode appears as cytoplasmic membrane loops that are contiguous with each layer of compacted
myelin membranes (►Fig. 2). Most of these membrane loops
abut the axolemma and are tightly tethered to the axon by
evenly spaced densities referred to as transverse bands. This
creates a scalloped narrowing of the myelinated axon that
defines three distinct structural domains: nodal, paranodal,
and juxtaparanodal. The node is a short stretch of bare
axolemma that separates paranodal domains of adjacent myelin segments. Nodal length is proportional to axon diameter
and can range from less than 1 μm in small fibers to more than
5 μm in large fibers. The paranode consists of the noncompact
myelin membrane loops and underlying axon segment. The
juxtaparanode is considered to be the 10 to 15 nm of myelin
internode adjacent to the paranodal domains.
Each structural domain contributes to saltatory conduction and is maintained by complex molecular interactions
that are still being defined. Nodal axolemma contains voltagegated Na+ channels and is thereby responsible for propagation
of action potentials. Juxtaparanodal axolemma contains voltage gated K+ channels and is thereby responsible for modulating the excitability of the node. Paranodal axolemma
contains adhesion molecules that participate in axoglial
junctions and thereby plays a role in spatially separating
Na+ and K+ channels.
Myelin Composition
Oligodendrocyte Development
Cells of the oligodendroglial lineage proceed through developmental stages characterized by differential expression of
surface antigens.1 Early oligodendrocyte progenitors are bipolar-shaped (two cellular processes), migratory and proliferative. Late progenitors retain proliferative capacity, but
begin to elaborate more processes. Proliferation then ceases,
cells enter terminal differentiation, and morphology becomes
more complex. The transition from immature to mature
oligodendrocyte is marked by the formation of myelin membranes. Throughout this process, lipids and proteins are
differentially expressed. Gangliosides GD3, GT3, and O-acetylated GT3 are expressed on the surface membrane of progenitors, but are subsequently downregulated as
differentiation proceeds. Mature myelin membranes are enriched in glycosphingolipids, primarily galactocerebroside
(GalC) and its sulfated derivative sulfatide. Similarly, myelin-specific proteins sequentially appear, and then shift
localization.
Membrane Polarization
Although the myelin sheath extends from the plasma membrane of the oligodendrocyte, myelin membranes differ significantly from the plasma membrane of the cell body. Myelin
is more than 70% lipids. In contrast, most plasma membranes
contain 30 to 50% lipids.2 In addition to lipid quantity, these
membranes differ further in terms of protein and lipid
composition. That is, various lipids and proteins are differentially expressed in myelin versus cell body membranes. There
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Paz Soldán, Pirko
Figure 2 The axon myelin unit. Mature oligodendrocytes extend processes that enwrap axons to form a multilayered membrane system, the
myelin sheath. Viewed in cross section (inset: electron micrograph), the myelin sheath displays a characteristic periodic structure with alternating
electron-dense (major dense line) and electron-light (intraperiod line) layers. Myelin basic protein fuses the cytoplasmic membrane leaflets to
form the major dense line, whereas proteolipid protein tightly apposes the outer membrane leaflets to form the intraperiod line. At the lateral
margins, myelin segments are composed of noncompact cytoplasmic loops that abut the axolemma (inset: electron micrograph) and form
junctional complexes. This defines distinct structural domains of axon-myelin contact: internode, juxtaparanode, paranode, and node. Functions
of many myelin-associated proteins are still being elucidated. Among these, adhesion proteins maintain axon-myelin contact, and through
cytoskeletal scaffolding proteins (not shown), cluster Na+ and K + channels at the node and juxtaparanode, respectively. Caspr, contactinassociated protein; Cntn, contactin; KCh, fast potassium channels; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; NaCh,
voltage-gated sodium channels; NECL, nectin-like protein/synCAM; NF155/186, neurofascin 155 kDa/186 kDa; Nr-CAM, neuronal cell adhesion
molecule; PLP, proteolipid protein. (Adapted with permission from Nave KA. Myelination and support of axonal integrity by glia. Nature 2010;468
(7321):244–252)
is also differential expression between compact and noncompact myelin membranes. The important consequence is
that myelinating oligodendrocytes contain two distinct membrane surfaces, the myelin membrane and the plasma membrane of the cell body, and can be considered as polarized
cells.
Development of the oligodendrocyte polarized phenotype
is central to the formation of myelin and requires coordinated
biogenesis, sorting, and trafficking of myelin membrane
components. Formation of this polarized phenotype is largely
analogous to that found in polarized epithelial cells. From a
membrane composition perspective, the myelin membrane
resembles the apical surface and the cell body membrane
resembles the basolateral.3 However, the vesicle-mediated
transport mechanisms that reach these membranes are unexpectedly the reverse. Namely, the myelin membrane is
reached by basolateral mechanisms and the cell body membrane by apical ones.4
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Biogenesis and Significance of Central Nervous System Myelin
Biogenesis and Significance of Central Nervous System Myelin
Lipids
Myelin and oligodendrocyte membranes contain cholesterol,
phospholipids, and glycosphingolipids (GSLs).Cholesterol and
GSLs are the major lipid components of myelin, making up
around 27% and 31% of total myelin lipids, respectively.5 The
GSLs found in myelin differ structurally from those found in
the plasma membranes of most other cell types. Namely, the
headgroup is based on galactose rather than glucose, very
long chain fatty acids are incorporated, and high levels of fatty
acid oxidation are present. Furthermore, within the myelin
membrane, GSLs are differentially located. GalC localizes to
compact myelin and sulfatide to noncompact myelin.6
Biosynthesis of myelin lipids is regulated by subcellular
compartmentalization. GSL synthesis is initiated on the cytoplasmic face of the endoplasmic reticulum (ER) with the
condensation of L-serine and palmitoyl-CoA, and the subsequent formation of ceramide through reduction, acylation,
and desaturation reactions.7 GalC is formed by the addition of
a galactose residue after ceramide has been flipped to the
luminal face of the ER. Subsequently, a portion of GalC is
converted to sulfatide on the luminal face of the Golgi.
Vesicular transport from the ER and Golgi, respectively,
facilitates the targeting of GalC and sulfatide to the outer
leaflet of the plasma membrane.8
Ceramide is the precursor for galactolipids, gangliosides,
and sphingomyelin.9 Once synthesized on the ER cytoplasmic
face, a portion of ceramide is also transferred to the Golgi
cytoplasmic face, where glucocerebroside (GlcC) is formed by
the addition of a glucose residue.10 GlcC is then flipped to the
luminal face of the Golgi, where lactosylceramide (LacC) is
formed by the addition of a galactose residue.11 LacC is the
precursor for most gangliosides, excluding GM4, which are
synthesized by the sequential action of sialyltransferases.
Similar to GalC and sulfatide, the gangliosides are targeted
to the outer leaflet of the plasma membrane by vesicular
transport.12
Cholesterol is felt to be poorly imported from systemic
pools; therefore, it must be synthesized in oligodendrocytes.13 Of note, the availability of cholesterol is a ratelimiting step in the elaboration of myelin.14 Synthesis occurs
in the ER, with subsequent transport through the Golgi and
insertion in the plasma membrane. The transport of cholesterol through the oligodendrocyte is incompletely understood, but may involve vesicular transport, direct
membrane contact, or cytoplasmic carriers.15
Proteins
Hundreds of myelin proteins have been detected by gel-based
proteome analysis.16 However, nearly 80% of the total protein
fraction of myelin is made up of two proteins: myelin basic
protein (MBP, 30%) and proteolipid protein (PLP, 50%). Both of
these proteins are integral to the formation of compact myelin
(►Fig. 2). MBP is a family of alternatively spliced extrinsic
membrane proteins.17 It is localized at the cytoplasmic
surface of compact myelin membranes where its high charge
binds negatively charged lipids, and thereby maintains the
major dense line.18 PLP is a hydrophilic integral membrane
protein with four membrane-spanning domains. Its extracelSeminars in Neurology
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lular domains form electrostatic interactions with myelin
lipids, and thereby maintain the intraperiod line.19
Numerous proteins are integral to the architecture of
noncompact myelin (►Fig. 2). The membrane proteins, contactin and Caspr, are expressed in paranodal axolemma
where they form heterodimers.20 Apposed paranodal loops
express an isoform of neurofascin (NF-155), which binds the
heterodimer21 to form axoglial junctions. Adjacent paranodal
loops are stabilized through adherens junctions containing Ecadherin and are interconnected through gap junctions containing connexin-47 and -32.22
Voltage-gated Na+ channels are clustered at the nodes of
Ranvier by a specialized cytoskeleton connected to a multimolecular membrane complex. In addition to the Na+ channels, nodal membrane proteins include neurofascin-186, NrCAM,23 and an isoform of Na+/K+-ATPase. The cytoskeleton
contains spectrin, f-actin, and two isoforms of ankyrinG.24
Voltage-gated K+ channels are similarly clustered at the
juxtaparanode, though the details are less characterized.
The cytoskeleton contains spectrin and f-actin, and membrane proteins include contactin-2 and Caspr-2.25
Myelin-associated glycoprotein (MAG) is an integral membrane protein containing five immunoglobulin-like domains.26
It is enriched in the periaxonal membrane27 where it functions, along with nectin-like proteins,28 to maintain spacing
and adhesion between the axon and myelin internode. MAG is
also enriched in the paranodal loops, where it maintains
spacing between adjacent membrane loops. Myelin membranes also contain numerous other specialized proteins,
many of which are not yet fully characterized.
Differential Expression of Proteins
As described above, the polarized phenotype of myelinating
oligodendrocytes has functional consequences. Individual
myelin proteins are often expressed, sorted, and transported
through different mechanisms to generate this polarity. The
two most common myelin proteins, PLP and MBP, provide
salient examples. Contrastingly, PLP is synthesized within the
oligodendrocyte soma before indirect transport to the myelin
membrane, whereas MBP is synthesized within myelin at the
site of myelin compaction.
PLP is synthesized in the endoplasmic reticulum, is transported via vesicles to the Golgi, initially localizes to the cell
body membrane, and is subsequently transported to the
myelin membrane. This indirect transport of PLP to the
myelin membrane suggests a transcytotic pathway similar
to that found in polarized epithelial cells, although the details
remain unclear. Targeting of PLP to the myelin membrane
requires palmitoylation at three N-terminal cysteine residues,29 and appears to require incorporation within cholesterol- and GalC-enriched membrane microdomains.30
MBP mRNA is exported from the nucleus, is assembled into
granules, is transported to its target site, and is subsequently
synthesized at the myelin membrane. Nuclear export is
regulated by RNA-binding proteins.31 In the cytoplasm, ribonucleoprotein complexes (granules) containing protein
translation components are assembled.32 Granules are then
transported along microtubules in a kinesin-dependent
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12
manner.33 Of note, MBP mRNA is targeted to the cell body or
to myelin, depending on the inclusion or exclusion of exon 2,
respectively.34 Docking at the target site and initiation of
protein synthesis are incompletely understood.
Myelin Function
Physiology
Historically, myelin was felt to be an inert membrane whose
low capacitance and high resistance alone facilitated rapid
and efficient propagation of action potentials. Current understanding, however, recognizes myelin as a dynamic participant in CNS physiology. In terms of impulse propagation, in
addition to its electrical insulative properties, myelin is
involved with the clustering of ion channels as described
above. Together, these features serve to increase conduction
velocity up to 100-fold for myelinated neurons.
Myelination also modulates the maturation, survival, and
regenerative capacity of axons through trophic support and
signaling molecules. Myelination, for example, enables an
axon to achieve its maximal diameter35 through modification
of the axonal cytoskeleton.36 Recently, myelin has been
proposed to supply the axon with chemical energy in the
form of ATP.37 Additionally, CNS myelin can inhibit neurite
development and axonal sprouting, as well as stabilize existing synapses. Surface membrane proteins, such as Nogo-A,
participate in these processes,38,39 whereas other members of
the Nogo family have been shown to be proapototic.40,41
These, and other described mechanisms, enable myelin to
facilitate communication between the axon, the oligodendrocyte, and the microenvironment.42 Given that oligodendrocytes are interconnected with each other and with astrocytes
through gap junctions,22 this communication network may
be far reaching.
Lipid composition of myelin also plays a critical role in
cellular communication. The maturation of oligodendrocytes,
coordinated production of myelin, control of axonal development, and support of axonal integrity is regulated by the
activation of various receptors and signaling molecules. The
availability of these molecules to transduce signals shifts
through the developmental process and is related to expression, localization, and access to binding partners. The enrichment of GSLs and cholesterol in myelin creates an
environment compatible with the formation of membrane
microdomains (lipid rafts). Lipid rafts serve to cluster appropriate signaling molecules, such as tyrosine kinase receptors,
G proteins, GPI-anchored proteins, adapter proteins, and
other important molecules for signal transduction.43–45
The mechanisms described above can have far-reaching
effects. Maturation of white matter can strengthen or inhibit
synaptic connections, thus reshaping connectivity on a network level.46 This is evidenced by recent work implicating
oligodendrocyte and myelin dysfunction in the development
of abnormal neural circuits.47
Pathophysiology
Myelin is produced through a complex process involving cell
differentiation, biosynthesis of specialized lipids and pro-
Paz Soldán, Pirko
teins, interaction with environmental signals, and coordinated changes in cell morphology. In terms of dysmyelinating
diseases, any of the molecules or processes described above
could be involved. First, the proliferation and differentiation
of oligodendroglia requires procession through multiple
stages of shifting trophic signals. Additionally, lipid and
protein biosynthesis requires the proper function of numerous molecules, the vesicular transport system, and the input
of energy. Strict control of intracellular transport is essential
in the assembly and maintenance of myelin. Finally, elaboration of myelin typifies a complex and shifting interaction
between the axon, the environment, and the myelinating cell.
In terms of demyelination, its complex structure and many
unique proteins leave myelin vulnerable to inflammatory
immune responses. Although healthy myelin membranes
are quite stable with turnover of components on the order
of weeks to months,48 myelin destruction necessitates a
dramatic increase in synthesis rates and the input of energy.
Furthermore, the loss of oligodendrocytes and availability of
progenitors may also be limiting. Specifically, although oligodendrocytes can produce multiple segments of myelin
across multiple axons, there appears to be a maximal amount
of myelin that can be supported. This is evidenced by the fact
that the number of internodes formed by a single oligodendrocyte is regulated by axon diameter,49 more for small axons
and less for large.
Myelin Disorders
Oligodendrocytes play a dual role: myelination and axonal
support. The primary disorders of myelin described in detail
in this issue manifest clinically with loss of function in each of
these roles. Understanding the pathophysiology of these
disorders, and the challenges faced in treating them, is
facilitated through understanding of the structure, function,
and generation/regeneration of myelin.
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