Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by acute focal demyelination, variable remyelination, and extensive neuronal and axonal degeneration [1
]. MS affects approximately 2.5 million people worldwide and is thought to be the most commonly acquired neurological disease of young adults.
There are 2 principal components in treating MS: 1) the prevention of damage, usually involving an immunomodulatory approach; and 2) the repair of damage, involving the regeneration of new myelin sheaths (remyelination) [2
]. Protection of neurons and their axons, the loss of which is the principal anatomical correlate of progressive clinical deterioration, might be considered a third component [4
]. Indeed, the overarching goal of all MS therapy is to identify strategies to prevent axonal loss. Axon protection can be achieved directly as a result of intervention in the mechanisms by which axons are injured or degenerate [5
]. However, axon protection can also be achieved as a consequence of immunomodulatory therapies and by the promotion of remyelination.
MS research for many decades has resulted in a considerable investment into the immunological aspects of the disease, as reflected in the identification of several immune-related genes as genetic determinants of disease susceptibility [6
] and an understanding of the disease pathogenesis [1
]. Although this research has proven to be highly informative and has translated into the development of highly effective immunomodulatory therapies, our knowledge pertaining to aspects of the disease is not directly related to immunology, but it is related to neurobiology instead, and specifically the interdependency between axon and oligodendrocytes remain relatively to be less explored [8
]. Thus, although immunomodulatory therapies are proving to be increasingly effective in controlling the initial relapsing-remitting phase of MS, the secondary progressive phase, in which there is continual atrophy of demyelinated axons, remains largely untreatable. Indeed, axon degeneration occurs despite immunomodulatory therapies, suggesting that axon integrity and protection may occur through mechanisms independent of inflammation [10
]. Several lines of evidence suggest that the basis of axon atrophy in chronically demyelinated lesions is due, in part, to the absence of myelin-associated trophic signals that are critical for maintaining axon integrity. For example, oligodendrocyte-specific deletions in myelin associated genes PLP, MAG, and CNPase do not cause any obvious defect in myelination, but eventually lead to axonal pathology [12
]. Moreover, axon degeneration has recently been observed as a consequence of genetically-induced oligodendrocyte-specific ablation [15
], thus providing compelling evidence that axon survival is dependent on intact oligodendrocytes, and that axon degeneration in chronically demyelinated lesions can occur independently of inflammation. The presence of low-grade inflammation (mainly cells of the innate immune response) has led to the suggestion that this inflammatory response may also contribute to progressive attritional axonal loss. However, it is far from clear whether this inflammation is a primary cause of axonal degeneration or a secondary response to axonal degeneration occurring due to loss of myelin-associated trophic support. Importantly, the increasing evidence of a role for myelin in preserving axon integrity reveals an evermore pressing need to understand the mechanisms of CNS remyelination.
In addition to preserving axon integrity [16
], remyelination also restores saltatory conduction and reverses functional deficits [18
]. Compelling evidence in support of functional restoration by remyelination has recently been provided by an unusual demyelinating condition in cats in which the reversal of clinical signs is associated with spontaneous remyelination [21
]. Taken together these observations imply that an effective means of restoring function and preventing axonal loss in MS is to promote remyelination.