Biology of Demyelinating Diseases 565
domains: MAG is selectively targeted to periaxonal membranes, PLP to compact
myelin, CNP to noncompact regions of the myelin internode, and MBP mRNA
to oligodendrocyte processes (Trapp et al., 2004). As described by Yakovlev and
Lecours (1966), myelination takes place until adult age and occurs at different ages
according to the area, the latest being the prefrontal area and the associative areas.
Thus leukodystrophies may start clinically in adulthood (Baumann and Turpin,
2000).
Axonal damage secondary to myelin loss is a major cause of sensory, motor, and
cognitive disabilities in adult MS (Bjartmar and Trapp, 2001). The lack of myelin
recovery may be due primarily to deficiency in the genesis of OPCs and in their
maturation in the adult CNS (Franklin, 2002; Stangel and Hartung, 2002). Limited
myelin regeneration is observed in early demyelinating lesions in MS (Wolswijk,
1998).
Possible explanations for remyelination failure in MS (Franklin, 2002; Stangel
and Hartung, 2002) can be the inadequate recruitment of OPCs (Keirstead et al.,
1998) or the inability of OPCs to turn into myelinating oligodendrocytes. Thus,
studies aiming at identifying factors involved in OPC differentiation during remyeli-
nation are of great interest. Guidance molecules Semaphorin 3A and 3F, already
known to direct oligodendroglial migration during development, may also be active
in controlling OPC migration in MS and may determine the ability of plaques to
remyelinate (Williams et al., 2007b).
It is conceivable that the process of remyelination mimics that of myelination
during development, but the key factors affecting the differentiation and maturation
of OPCs into myelinating oligodendrocytes do not perfectly trigger remyelination
in the adult brain.
4.3 Biochemical Factors
As noted above, myelination requires a tightly regulated balance between the
disappearance of inhibitory signals, and the induction of positive signals.
Adhesion molecules. The downregulation of the polysialylated neuronal cell
adhesion molecule (PSA-NCAM) from the axonal surface (Charles et al., 2000)

is a necessary prerequisite to render the axon permissive to myelination (Charles
et al., 2002; Coman et al., 2005). L1, another adhesion molecule expressed at the
axonal surface, promotes myelination (Coman et al., 2005).
In demyelination such as MS, PSA-NCAM is expressed on denuded axons and
might act as an inhibitor of remyelination, whereas the myelinated part outside the
plaque is PSA-NCAM negative (Charles et al., 2000; Coman et al., 2005). On the
other hand, in MS a two- to threefold increase in OPC density and proliferation was
found in the subventricular zone (SVZ), which correlated with enhanced numbers
of PSA-NCAM(+) cells (Nait-Oumesmar et al., 2007). EAE in rodents is another
important example of the activation of the SVZ and the involvement of progenitor
cells expressing the polysialylated form of neural cell adhesion molecule (PSA-
NCAM) in the repair process (Picard-Riera et al., 2002).
566 D. Pham-Dinh and N. Baumann
4.3.1 Growth Factors and Transcription Factors
PDGF alpha and laminin. Laminin-2 deficient mice demonstrate the crucial role
of laminin-2 in CNS myelination (Chun et al., 2003). Survival of oligodendrocytes
that contact axons requires laminin. In the absence of laminin, the concentration
of survival factors such as PDGF is too low to promote survival of newly formed
oligodendrocytes. Oligodendrocytes that contact laminin on axon tracts initiate inte-
grin signaling that amplifies the survival response by PDGF. Oligodendrocytes that
contact axons are then able to survive and myelinate (Colognato et al., 2005).
When α6β1 integrin on the oligodendrocyte binds axonal laminin, Fyn (a member
of the Src family kinase) is activated, promoting oligodendrocyte differentiation.
Fyn knock-out and α2 laminin knock-out exhibit similar region-specific pheno-
types, with a severe myelin deficit in the forebrain in contrast to normal appearing
myelin in the spinal cord (Camara and Ffrench-Constant, 2007; Chun et al., 2003).
Dystroglycan is a second laminin receptor in oligodendrocytes that expresses and
uses this receptor to regulate myelin formation. Blocking the function of dystrogly-
can receptors leads oligodendrocytes to fail to produce complex myelin membrane
sheets and to initiate myelinating segments when cocultured with dorsal ganglion

neurons (Colognato et al., 2007).
J agged is developmentally regulated in neurons and activates the Notch pathway
in OPCs, which inhibits their differentiation into oligodendrocytes (Givogri et al.,
2002). Because Jagged decreases with a time course that parallels myelination, it is
likely that neurons help to regulate the timing of myelination. In the demyelinating
brain, the inappropriate upregulation of molecules, including those of the Jagged-
1-Notch-1 signal transduction pathway, affects OPC differentiation (Mastronardi
and Moscarello, 2005). The importance of communication between astrocytes and
oligodendrocytes was also demonstrated in MS in which the abnormal expression
of Jagged 1 by reactive astrocytes could be responsible for the failure of myelin
repair following myelin destruction caused by inhibition of progenitor differentia-
tion (John et al., 2002). However, in the mouse model, remyelination can proceed
to completion despite widespread Notch–Jagged expression; thus Notch–Jagged
signaling is not a rate-limiting determinant of remyelination in rodent models of
demyelination (Stidworthy et al., 2004).
The neuregulins (NRGs) constitute a family of proteins containing an epidermal
growth factor (EGF)-like domain that activates the membrane associated ErbB2,
ErbB3, ErbB4 receptor tyrosine kinases. NRGs activate ErbBs on oligodendro-
cytes in the developing CNS. In the absence of ERBb signaling, oligodendrocytes
fail to undergo terminal differentiation and to ensheath axons (Park et al., 2001a,
b). Loss of erbB signaling, by expression of a dominant negative erbB recep-
tor transgene, in oligodendrocytes alters myelin and dopaminergic function (Roy
et al., 2007). These transgenic mice have increased levels of dopamine receptors
and transporters, and exhibit behavioral alterations consistent with neuropsychiatric
disorders. These results indicate that defects in white matter can cause alter-
ations in dopaminergic function and behavior relevant to neuropsychiatric disorders
(Roy et al., 2007).
Biology of Demyelinating Diseases 567
There are several subgroups of NRG among which are NRG1 type III. Axonal
NRG1 regulates myelin sheath thickness in the PNS (Michailov et al., 2004).

NRG1 type III, independent of axon diameter, provides a key instructive sig-
nal that determines the ensheathment fate of axons (Taveggia et al., 2005).
Ensheathed axons express low levels whereas myelinated fibers express high levels
of NRG1 type III. Type III is the sole NRG1 isoform retained at the axon sur-
face and activates phosphatidylinositol 3-kinase, which is required for Schwann cell
myelination.
Oligodendrocytes also respond to insulin growth factor IGF-1 that stimulates
oligodendrocyte growth and prevents oligodendrocyte apoptosis. Overexpression of
IgF-1 increases the percentage of myelinated axons and the thickness of myelin
sheaths. IGF type 1 receptor is required for normal in vivo development and
myelination (Zeger et al., 2007). The association of transferring and IGF-1 favors
remyelination in the myelin-deficient rat (Espinosa-Jeffrey et al., 2006).
Olig1 and Olig2 encode basic helix–loop–helix (bHLH) transcription factors
that are expressed in both the developing and mature CNS. Expression of Olig
in human brain tumors and demyelinating lesions suggest the possibility of addi-
tional functions in a variety of neurological diseases (Ligon et al., 2006; Zhao
et al., 2005). Mice lacking a functional Olig1 gene develop severe neurological
deficits and die in the third postnatal week. In the brains of these mice, expres-
sion of myelin-specific genes is abolished, whereas the formation of OPCs is not
affected. Furthermore, multilamellar wrapping of myelin membranes around axons
does not occur, despite recognition and contact of axons by oligodendrocytes, and
Olig1-null mice develop widespread progressive axonal degeneration and gliosis. In
contrast, myelin sheaths are formed in the spinal cord, although the extent of myeli-
nation is severely reduced. At the molecular level, Olig1 regulates transcription of
the major myelin-specific genes, MBP, PLP1, and MAG, and suppresses expres-
sion of a major astrocyte-specific gene, Gfap. Thus Olig1 is a central regulator of
oligodendrocyte myelinogenesis in brain, and axonal recognition and myelination
by oligodendrocytes are distinct processes (Xin et al., 2005).
Eukaryotic initiation factor 2B (elF2B) is a five-subunit guanine nucleotide
exchange factor that exchanges GDP for GTP to form the elF2B-GTP complex.

e1F2B mutations lead to an abnormal control of protein translation that predom-
inantly affects glial cells. Mutations in elF2B (Leegwater et al., 2001) cause one
of the most common leukodystrophies: childhood ataxia with CNS hypomyelina-
tion/vanishing white matter disease or CACH/VWM (reviewed in Schiffmann and
Elroy-Stein, 2006). Astrocytes are affected (Dietrich et al., 2005), oligodendro-
cytes are overcrowded (Rodriguez et al., 1999) and become foamy, and neurons are
spared. The disease is autosomal dominant. There is a cystic breakdown of white
matter or “cavitation” and no gadolinium enhancement of the lesions on MRI. The
disease can be caused by mutations in any of the five subunits of elF2B.
Qk1 (quaking). The quaking viable (qkv) is a spontaneous recessive mutation in
the mouse that deletes an enhancer of the qkI gene and causes diminished qkI tran-
scription, specifically in myelin-producing cells. The qkv mice provide a unique
animal model linking RNA binding proteins to defects in oligodendrocyte cell fate
568 D. Pham-Dinh and N. Baumann
and myelination (Larocque and Richard, 2005). The qkI gene encodes RNA bind-
ing proteins that are involved in the transport of myelin-specific RNAs, such as
those encoding myelin basic proteins (MBP), to specific cellular locations for trans-
lation. Schizophrenia, a severe mental disorder, comprising social and cognitive
defects may be linked to a qk susceptibility locus (Aberg et al., 2006; Lindholm
et al., 2001). QKI, which is essential for myelination, is decreased in schizophrenia
(McInnes and Lauriat, 2006). Downregulation of QK1 might be among the pri-
mary causes of downregulation of myelin-related genes in schizophrenia (Karoutzou
et al., 2007).
The major cognitive disturbances in schizophrenia may result from a deficit of
myelination in relevant neuronal structures, such as the corpus callosum, involved
in connectivity between both hemispheres; the resulting decrease of electrical con-
duction in fiber tracks linking different parts of the brain may affect behavior and
perception (Haroutunian and Davis, 2007; Haroutunian et al., 2007).
Transferrin (Tf), the iron transport glycoprotein found in the biological fluids of
vertebrates, is also synthesized by oligodendrocytes in the CNS. Overexpressing Tf

in the brain of transgenic mice accelerates oligodendrocyte maturation, early mat-
uration of the cerebellum and spinal cord, and myelination in the corpus callosum
(Sow et al., 2006). The association of IGF-1 and transferrin favors remyelination in
the myelin deficient rat (Espinosa-Jeffrey et al., 2006).
Neurotransmitters. Numerous neurotransmitters affect the development of oligo-
dendrocytes. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
and kaïnate receptors are expressed on oligodendrocytes. Glutamate has an
inhibitory role in the proliferation of oligodendrocytes, especially in relation to
AMPA and NMDA receptors (Karadottir and Attwell, 2007). Indeed, glutamate
can be toxic to white matter oligodendrocytes through AMPA, kainate gluta-
mate receptor, and N-methyl-D-aspartate receptors (NMDA) (Matute, 2006). Drugs
that interact with glutamate receptors in experimental models of MS can con-
tribute to a more favorable outcome (Bolton and Paul, 2006). Dopamine D3
and D2 receptors are also present as well as GABAa receptors. Their roles are
not yet elucidated. In experimental models of demyelinating diseases (Theiler’s
virus) cannabinoids reduce microglial activation, abrogate major histocompatibility
complex Class II antigen expression, and decrease the number of CD4+ infiltrat-
ing T cells (Arevalo-Martin et al., 2003). N-acetyl aspartate is synthesized from
aspartate and acetyl coenzyme A in neurons. The NAA-degrading enzyme is N-
aspartoacylase (ASPA). ASPA cleaves the acetate moiety for use in fatty acid
and steroid derivatives. Mutations in the gene coding for ASPA result in Canavan
disease, a fatal leukodystrophy (Moffett et al., 2007).
Second messengers: Adenosine, ATP, and LIF. Adenosine regulates proliferation
and differentiation of OPCs (Stevens et al., 2002), whereas ATP affects mature
oligodendrocytes. ATP does not act directly on oligodendrocytes but rather on
astrocytes, causing the release of LIF (leukaemia inhibitory factor) by these cells,
which in turn triggers the myelination process by promyelinating oligodendrocytes
(Ishibashi et al., 2006; Simons and Trajkovic, 2006). However, in LIF-deficient
Biology of Demyelinating Diseases 569
animals, myelin may be formed in the absence of LIF (Bugga et al., 1998),

indicating that other factors/cytokines, may complement for that function.
By contrast to oligodendrocytes (Lubetzki et al., 1993), Schwann cells abso-
lutely need the presence of neurons to differentiate and myelinate in vitro (Jessen
and Mirsky, 1991; Owens and Bunge, 1989). As for oligodendrocytes in the
CNS, calcium imaging in glia in the PNS revealed that purinergic receptors allow
premyelinating Schwann cells to detect action potential firing, due to ATP released
from axons (Stevens and Fields, 2000; Stevens et al., 2004). Different purinergic
receptors (Fields, 2006) are expressed on both types of glia resulting, however,
in opposite effects of impulse activity on differentiation of Schwann cells and
OPC. In the PNS, ATP regulates early development and myelination by Schwann
cells, whereas it inhibits differentiation and myelination (Jessen and Mirsky, 1991),
in striking contrast to what happens in the CNS (Stevens, 2006). Both ATP and
adenosine inhibit proliferation of Schwann cells induced by PDGF. Unlike ATP,
adenosine failed to inhibit differentiation of Schwann cells, in contrast with its role
in oligodendrocyte differentiation in the CNS (Stevens et al., 2004).
Hormones. It is well established that thyroid hormone (TH) is required for the
normal timing of OPCs differentiation and maturation (Rogister et al., 1999). Also,
normal cell-cycle progression mechanisms and terminal differentiation and matu-
ration require TH (Durand and Raff, 2000). Studies of myelination in hypo- and
hyperthyroid animals (Jagannathan et al., 1998) have provided strong evidence that
TH plays an important role in regulating oligodendrocyte lineage and maturation in
vivo and that the TH receptor α1 seems to be responsible for this process (Billon
et al., 2002). The administration of TH during the acute phase of experimental aller-
gic encephalomyelitis (EAE) in rats, a commonly used experimental model for MS,
is able to generate oligodendroglial cells (Calza et al., 2002).
Steroid hormones: Androgens. Interestingly, a sexual dimorphism of oligoden-
drocytes and myelin has been demonstrated in rodents. The density of oligoden-
drocytes in corpus callosum, fornix, and spinal cord is 20–40% greater in males
compared with females, independent of age, strain, and species of rodent. This
is associated with an elevated level of PLP and CAII (carbonic anhydrase 2).

Moreover, oligodendrogenesis and apoptosis of glia are two times greater in female
corpus callosum, indicating that the lifespan of oligodendrocytes is shorter in
females than in males. Castration of males produces a female phenotype charac-
terized by fewer oligodendrocytes and increased generation of new glia (Cerghet
et al., 2006). In EAE castration of males increased the severity of the disease
(Bebo et al., 1998) whereas in MS, the lowest levels of serum testosterone in
affected women correlates with the severity of the disease, again indicating that
androgens are protective (Tomassini et al., 2005), possibly more than estrogens.
Altogether, these data indicate that exogenous androgens differentially affect the
lifespan of male and female oligodendrocytes, and can override the endogenous
production of neurosteroids. These data imply that the turnover of myelin is greater
in females than in males, a process that may account for more myelin break-
down products in females. These findings have a potential significance for MS, a
570 D. Pham-Dinh and N. Baumann
sexually dimorphic disease, whose progression is altered by exogenous hormones
(Cerghet et al., 2006).
The steroid hormones progesterone and derivatives promote the viability of neu-
rons in the CNS and play an important role in developmental myelination and
in myelin repair. The hormone may promote neuroregeneration by several differ-
ent actions—reducing inflammation, swelling, and apoptosis—thereby increasing
the survival of neurons, and promoting the formation of new myelin sheaths.
Recognition of the important pleiotropic effects of progesterone opens novel
perspectives for the treatment of brain lesions and diseases of the nervous system.
Exogenous administration of progesterone or some of its metabolites can be suc-
cessfully used to treat traumatic brain and spinal cord injury, as well as ischemic
stroke (reviewed in Schumacher et al., 2007). Progesterone can be synthesized by
neurons and by glial cells within the nervous system, as neurosteroids (Jung-Testas
et al., 1999). This finding opens the way for the use of pharmacological agents, such
as ligands of TSPO (translocator protein), the peripheral benzodiazepine receptor, to
locally increase the synthesis of steroids with neuroprotective and neuroregenerative

properties (reviewed in Schumacher et al., 2007).
Prolactin. Motherhood has been shown to attenuate t he age-related decline in
learning and memory in the rat (Gatewood et al., 2005). Remission of MS dur-
ing pregnancy led to the hypothesis that remyelination is enhanced in the maternal
brain. In MS, the elevated prolactin levels during pregnancy may allow myelin
repair, during a temporal window when there is a shift from proinflammatory Th1
to anti-inflammatory Th2-mediated immunity. Using animal models, it has been
shown that prolactin treatment promotes myelin repair in female mice (Gregg et al.,
2007), mimicking the regenerative effect of pregnancy on white matter damage.
Prolactin induces changes early in pregnancy: increased oligodendrogenesis, MBP
expression, and the number of myelinated axons. Remarkably, pregnant mice have
an enhanced ability to remyelinate white matter lesions. The hormone prolactin reg-
ulates oligodendrocyte precursor proliferation and mimics the regenerative effects
of pregnancy.
5 Conclusion
Our knowledge of myelin constituents has greatly increased, as well as the role of a
bidirectional dialogue between glial cells and neurons in myelination and demyeli-
nation; but, little is known of the mechanisms responsible for myelin repair. Why is
remyelination incomplete with less myelin and shorter internodes?
Many mysteries remain about the timing of myelination and demyelination, as
many genetic diseases become manifest only in adulthood. There is a time and
regional control of myelination and demyelination as, for instance, in the cuprizone
model. That only implicates certain brain areas, but we know very little about it.
A variety of pathogenic mechanisms has been shown to be at work in myelin
diseases: point mutations, recombination events leading to deletions, and duplica-
tion of genomic regions including myelin genes. The exquisite sensibility to gene
Biology of Demyelinating Diseases 571
dosage of myelinating glial cells has been pointed out in human myelin diseases
as in genetically modified animal models. Nevertheless, there is not always a phe-
notype/genotype relationship, indicating that many factors involved still remain

unknown in human demyelinating diseases. New areas of research are being devel-
oped showing the involvement of myelin deficiency in psychiatric diseases and
cognition.
Although the roles of major constituents of myelin in relation to pathological
experimental models are clear, the specific mechanisms i n many human diseases
still need to be investigated.
Acknowledgments Drs Saïd Ghandour and Jean-Claude Turpin are gratefully acknowledged for
their help and advice during the redaction of this manuscript, and Eric Noe for the careful reading of
text and references. The research work of the authors is supported by grants from ELA Foundation
(European Leukodystrophy Association), Association Jerome Lejeune, and INSERM to DP-D, and
ARNC (association pour la recherche en neurochimie) to NB.
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