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Axonal dysfunction in chronic multiple sclerosis Meltdown in the membrane.

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EDITORIALS
Axonal Dysfunction in
Chronic Multiple Sclerosis:
Meltdown in the Membrane
It is well established that the axon membrane plays an
important role in the pathophysiology of multiple sclerosis (MS). Along healthy myelinated axons, voltagegated sodium channels are clustered at the nodes of
Ranvier where they are needed for saltatory conduction, whereas the internodal axon membrane, which is
normally covered by the myelin, does not contain
enough sodium channels to support secure impulse
conduction. Importantly, however, the density of sodium channels can increase in the denuded (previously
myelinated and previously sodium channel poor) axon
membrane in some demyelinated axons. This remarkable molecular adaptation provides a basis for restoration of impulse conduction in these fibers.1 Sodium
channels within the axon membrane can also play a
maladaptive role by providing a route for sustained sodium influx that drives reverse (calcium-importing)
sodium-calcium exchange, which can trigger the activation of an ensemble of injurious molecules including
proteases and lipases within energetically challenged axons.2,3
In this issue of Annals, Young and colleagues4 report
the presence of Na⫹/K⫹ ATPase, which is deployed in
a uniform pattern along substantial lengths of the internodal axon membrane of myelinated nerve fibers
within control human brain. They note a similar, relatively high level of expression along axons in acute
MS lesions. In contrast, they report substantially reduced Na⫹/K⫹ ATPase, and absence of detectable
Na⫹/K⫹ ATPase in some instances, along the axon
membrane within chronic MS lesions (Fig). These new
observations build on an earlier report of reduced
Na⫹/K⫹ ATPase enzymatic activity within chronic MS
lesions.5 The observations on Na⫹/K⫹ ATPase also
add to recent and similar observations on sodium
channels indicating that, although these channels are
diffusely distributed along extensive regions of demyelinated axons within acute MS lesions,6 they are expressed at substantially lower levels, in a patchy rather
than continuous distribution, along axons within
chronic MS lesions.7 The common theme is that there
is a deterioration of expression or maintenance of both
sodium channels and Na⫹/K⫹ ATPase in the chronically demyelinated axon membrane. Also indicating a
change in integrity of the axon membrane, there is also
evidence for an abnormal spatial distribution of paranodal and juxtaparanodal proteins such as Caspr and
Caspr2 along demyelinated axons in MS.8,9 Taken together, these observations suggest that, in some cases,
there is generalized breakdown in architecture of the
axon membrane after long-term demyelination in MS.
Both Na⫹/K⫹ ATPase and sodium channels play
pivotal roles in the physiological activity of axons
within the central nervous system: Na⫹/K⫹ ATPase
helps to maintain appropriate ionic gradients across the
axon membrane and, although not contributing to the
repolarization phase of the action potential (which is
due to rapid inactivation of sodium channels and possibly to the opening of potassium channels), it restores
transmembrane gradients of sodium and potassium after activity so that axons can maintain their resting potentials and conduct repetitive trains of impulses. Sodium channels play an essential role in the generation
of action potentials, producing a rapid influx of sodium ions that underlies the depolarizing phase of the
impulse. Like the paucity of sodium channels in
chronic MS lesions,7 the paucity of Na⫹/K⫹ ATPase
along a subpopulation of chronically demyelinated axons suggests that these fibers can become electrically
incompetent, a factor that would be expected to contribute to clinical disability even before axonal degeneration.
The mechanisms responsible for the reduced levels
of sodium channels and Na⫹/K⫹ ATPase along chronically demyelinated axons are not yet understood. One
possibility is that the low level of these molecules is a
result of proteolysis by calcium-activated enzymes.10 It
is also possible that loss of contact with myelinating
glial cells or myelin, or reduced exposure to trophic
factors produced by myelinating glial cells, leads to a
breakdown in the axon membrane, or that there is reduced expression of genes encoding sodium channels
or ATPase within neurons, as has been suggested11 for
genes encoding respiratory chain molecules in MS lesions. With respect to Na⫹/K⫹ ATPase, it is known
that in some cell types sodium channels provide a
pathway for return of sodium ions to the cytoplasm,
which is necessary for operation of Na⫹/K⫹ ATPase.
This functional linkage between sodium channels and
Na⫹/K⫹ ATPase has been clearly demonstrated in astrocytes,12 which express sodium channels in their cell
membranes but do not, under normal circumstances,
produce action potentials,13 and there is some evidence
suggesting that there may be a similar linkage of sodium channel and Na⫹/K⫹ ATPase operation in myelinated axons within central nervous system white
matter.14 The dependence of Na⫹/K⫹ ATPase activity
on influx of sodium ions through sodium channels
raises the question of whether altered levels of sodium
channel expression in chronically demyelinated axons
might lead to a change in Na⫹/K⫹ ATPase expression.
It is also unclear whether the reduced axonal
Na⫹/K⫹ ATPase levels in chronic MS lesions are a
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
411
Fig. Diagrammatic representation of myelinated and demyelinated axons showing putative changes in axon membrane architecture. (A) In normal myelinated axons, clustering of sodium channels at the node, and expression of Na⫹/K⫹
ATPase along the internode, support secure action potential
conduction. (B) In early stages of demyelination, loss of the
myelin capacitative shield together with lack of a sufficient
number of sodium channels in the denuded axon membrane
results in conduction failure. (C) At later stages after demyelination, some axons deploy a higher density of sodium channels
along regions devoid of myelin, supporting impulse conduction
in these demyelinated zones. (D) Axonal degeneration occurs
and interrupts conduction in some fibers. (E) Axon membrane
deterioration, with failure to maintain adequate densities of
sodium channels and Na⫹/K⫹ ATPase in areas devoid of myelin, produces conduction block in other fibers that have not
yet degenerated within chronic multiple sclerosis lesions.
cause or a result of axonal injury. Reduced Na⫹/K⫹
ATPase levels might be expected to lead to increased
concentrations of intraaxonal sodium; this could, as
in anoxic white matter, trigger reverse (calciumimporting) sodium-calcium exchange, which, in turn,
would activate injurious enzymes within the axon.
However, the paucity of sodium channels along axons
in these chronic lesions reduces one source of sodium
influx, both at rest and during the generation of action
potentials. Absence of high-frequency impulse activity
in axons lacking sufficient numbers of sodium channels
would limit the sodium influx even in fibers that could
generate low-frequency impulse trains. Alternatively,
decreased levels of Na⫹/K⫹ ATPase within chronically
demyelinated axons could be a result of axonal injury.
Calcium influx and impaired calcium buffering mechanisms associated with axonal injury might lead to
damage to protein subunits of the Na⫹/K⫹ ATPase or
of associated protein molecules that are important for
412
Annals of Neurology
Vol 63
No 4
April 2008
Na⫹/K⫹ ATPase expression or activity. It is also possible that axonal injury could trigger changes in gene
expression within the neuronal cell bodies, including a
downregulation of expression of genes encoding
Na⫹/K⫹ ATPase subunits or essential partner molecules.
An important bottom line of Young and colleagues’4
results and Black and coworkers’7 earlier results is that
membrane abnormalities in chronically demyelinated,
but still intact, axons may impair the ability of these
still-surviving fibers to conduct impulses, and thus contribute to disability in chronic MS. Stated differently,
failure of conduction in a subpopulation of chronically
demyelinated axons is likely to produce a functional
deficit in MS, even before degeneration of these fibers.
Thus, clinical progression of MS may be due not only
to axonal degeneration but also to other factors including failure to maintain the axon membrane architecture
needed to support impulse conduction along chronically demyelinated axons that have not degenerated.
Interestingly, although the level of expression of axonal Na⫹/K⫹ ATPase was decreased in chronic MS
plaques, Young and colleagues4 observe that a subpopulation of axons in some of these lesions continued
to express Na⫹/K⫹ ATPase. Similarly, Black and coworkers7 observed that one-third of axons in chronic
MS lesions displayed sodium channel immunostaining
that was distributed along the axons in a multifocal,
patchy pattern rather than a continuous distribution.
There is, in fact, evidence that a patchy distribution of
sodium channels, which can be deployed nonuniformly
along some nonmyelinated and demyelinated axons in
nodelike islands even in the absence of myelin,15 can
support pseudosaltatory conduction of impulses, at
least at low frequencies.16 Whether the residual
Na⫹/K⫹ ATPase and sodium channels seen along demyelinated axons in chronic MS lesions by Young and
colleagues4 and Black and coworkers7 help to maintain
axonal impulse conduction is not yet known.
In the aggregate, the recent findings suggest that, in
at least some axons within chronic MS lesions, damage
to the electrogenic machinery impairs impulse conduction, contributing to clinical deterioration, before axonal degeneration. This could have therapeutic
implications. Protection of functional or potentially
functional axons, that is, axons that have retained the
capability to securely conduct impulses or can regain it,
remains an important therapeutic strategy for MS.17 In
contrast, protection of axons that have lost the capability to support reliable action potential transmission
would not be expected to improve clinical outcome.
This raises the questions of whether it might be possible to develop therapeutic interventions that would
maintain a complement of ion channels and pumps
that would support impulse conduction within these
axons, and if so, whether these axons could sustain the
ion fluxes associated with this molecular machinery
without degenerating. If so, this could provide an alternative strategy, in addition to protective approaches
that prevent axonal degeneration, that might slow the
progression of disability in MS.
16. Smith KJ, Bostock H, Hall SM. Saltatory conduction precedes
remyelination in axons demyelinated with lysophosphatidylcholine. J Neurol Sci 1982;54:13–31.
17. Waxman SG. Sodium channels and neuroprotection in MS:
current status. Nat Clin Pract Neurol (in press).
DOI: 10.1002/ana.21361
Stephen G. Waxman, MD, PhD
Department of Neurology and Center for Neuroscience
and Regeneration Research
Yale University School of Medicine
New Haven, CT
and VA Connecticut Healthcare
West Haven, CT
References
1. Waxman SG. Current concepts in neurology: membranes, myelin and the pathophysiology of multiple sclerosis. N Engl
J Med 1982;306:1529 –1533.
2. Stys PK, Waxman SG, Ransom BR. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na⫹
channels and Na⫹-Ca2⫹ exchanger. J Neurosci 1992;12:
430 – 439.
3. Waxman SG, Black JA, Stys PK, Ransom BR. Ultrastructural
concomitants of anoxic injury and early post-anoxic recovery in
rat optic nerve. Brain Res 1992;574:105–119.
4. Young EA, Fowler CD, Kidd GJ, et al. Imaging correlates of
decreased axonal Na⫹/K⫹ ATPase in chronic multiple sclerosis
lesions. Ann Neurol 2008;63;428 – 435.
5. Hirsch HE, Parks ME. Na⫹ and K⫹ dependent adenosine
triphosphatase changes in multiple sclerosis plaques. Ann Neurol 1983;13:658 – 663.
6. Craner MJ, Newcombe J, Black JA, et al. Molecular changes in
neurons in MS: altered axonal expression of Nav1.2 and Nav1.6
sodium channels and Na⫹ /Ca2⫹ exchanger. Proc Natl Acad
Sci USA 2004;101:8168 – 8173.
7. Black JA, Newcombe J, Trapp BD, Waxman SG. Sodium
channel expression within chronic MS plaques. J Neuropath
Exp Neurol 2007;66:828 – 838.
8. Coman J, Aigrot MS, Seilbean D, et al. Nodal, paranodal and
juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 2006;129:3186 –3195.
9. Wolswijk G, Balesar R. changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain 2003;126:1638 –1649.
10. Stys PK, Jiang Q. Calpain-dependent neurofilament breakdown
in anoxic and ischemic rat central axons. Neurosci Lett 2002;
328:150 –154.
11. Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006;59:478 – 489.
12. Sontheimer H, Fernandez-Marques E, Ullrich N, et al. Astrocyte Na⫹ channels are required for maintenance of Na⫹/K⫹ATPase activity. J Neurosci 1994;14:2464 –2475.
13. Sontheimer H, Waxman SG. Ion channels in spinal cord astrocytes in vitro: II. Biophysical and pharmacological analysis of
two Na⫹ current types. J Neurophysiol 1992;68:1000 –1011.
14. Stys PK, Sontheimer H, Ransom BR, Waxman SG. Noninactivating, TTX-sensitive Na⫹ conductance in rat optic nerve
axons. Proc Natl Acad Sci USA 1993;90:6976 – 6980.
15. Hildebrand C, Waxman SG. Regional node-like membrane
specializations in non-myelinated axons of rat retinal nerve fiber
layer. Brain Res 1983;258:23–32.
Congenital Hemiplegia: Not
Only Caused by Presumed
Perinatal Arterial Stroke
In this issue of Annals, Kirton and colleagues1 report
on lesion patterns including periventricular venous infarction (PVI) of presumed antenatal onset, preceding
the postnatal development of hemiplegia. Until now,
stroke of presumed antenatal or perinatal timing has
been restricted to infants, who present with pathological handedness (hand preference earlier than 1 year
of age) and/or seizures at or after 2 months of age, or
occasionally with other neurological problems for
which brain imaging shows an ischemic, usually arterial territory stroke. In a recent population-based, case–control study,2 presumed perinatal ischemic stroke
(recently given the acronym PPIS) was present in 17
of 100,000 live births. Of the 38 cases, the majority
(n ⫽ 26; 68%) presented after 3 months from birth
with hemiparesis or seizures, and computed tomography or magnetic resonance imaging confirmed an established stroke in arterial distribution in all cases.
Another study from the Canadian Pediatric Ischemic
Stroke Registry identified 22 infants with PPIS.3
A few children with hemiplegia, with presumed antenatal or perinatal onset of a unilateral parenchymal hemorrhage (known as “venous infarction” in the preterm
infant), were recently reported and referred to as perinatal venous infarction (PVI).4,5 This type of hemorrhage
with subsequent evolution into a porencephalic cyst is a
condition that is seen in 5 to 8% of very low-birthweight infants and is considered to be caused by impaired venous drainage from the medullary veins in the
periventricular white matter.6 A hemiplegia will result if
the region of the trigone is involved, and appropriate
and symmetric myelination of the internal capsule is not
achieved by term-equivalent age.7 The incidence of this
type of lesion increases with decreasing gestational age,
and the diagnosis is mostly made after birth in preterm
infants born before the gestational age of 30 completed
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
413
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