Overcoming remyelination failure in multiple sclerosis and other myelin disorders

Abstract

Protecting axons from degeneration represents a major unmet need in the treatment of myelin disorders and especially the currently untreatable secondary progressive stages of multiple sclerosis (MS). Several lines of evidence indicate that ensuring myelin sheaths are restored to demyelinated axons, the regenerative process of remyelination, represents one of the most effective means of achieving axonal protection. Remyelination can occur as a highly effective spontaneous regenerative process following demyelination. However, for reasons that have not been fully understood, this process is often incomplete or fails in MS. Recognizing the reasons for remyelination failure and hence identifying therapeutic targets will depend on detailed histopathological studies of myelin disorders and a detailed understanding of the molecular mechanisms regulating remyelination. Pathology studies have revealed that chronically demyelinated lesions in MS often fail to repair because of a failure of differentiation of the precursor cell responsible for remyelination rather than a failure of their recruitment. In this article we review three mechanisms by which differentiation of precursor cells into remyelinating oligodendrocytes are regulated–the Notch pathway, the Wnt pathway and the pathways activated by inhibitor of differentiation in myelin debris–and indicate how these might be pharmacologically targeted to overcome remyelination failure.

Introduction

When the first pathological descriptions of multiple sclerosis (MS) were made at the end of the 19th century and the beginning of the 20th century two cardinal features of the disease were identified: first, acute inflammation associated with primary demyelination and second, axonal dystrophy and loss. The intervening decades have seen a considerable investment into the immunological aspects of the disease, reflected in the identification of several immune-related genes as genetic determinants of disease susceptibility (Oksenberg, et al., 2008) and an understanding of the disease pathogenesis that has translated into the development of highly effective immunomodulatory therapies (Coles et al., 2008, Compston and Coles, 2008).

Paradoxically, the success of this line of MS research has thrown into relief deficiencies in our understanding of aspects of the disease not directly related to immunology but that instead relate to neurobiology and in particular the interdependency between the axon and oligodendrocyte (Nave and Trapp, 2008). Thus, while immunomodulatory therapies are proving increasingly effective in controlling the initial relapsing-remitting phase of MS, the secondary progressive phase, in which there is a continual atrophy of demyelinated axons, remains untreatable. This occurs despite immunomodulatory therapies suggesting a mechanism independent of inflammation (Coles et al., 1999, Dutta and Trapp, 2007). 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 leads to axonal pathology (Griffiths et al., 1998, Lappe-Siefke et al., 2003, Li et al., 1994). Similarly, the substitution of PLP with the peripheral myelin protein P₀ in mice leads to axonal dystrophy, implying an as yet uncharacterized trophic role for PLP in axonal maintenance (Yin et al., 2006).

These observations imply that an effective means of preventing axonal loss might be more efficacious myelin restoration. This process, called remyelination or, less accurately, myelin repair, can occur as a spontaneous regenerative process following demyelination (Duncan et al., 2009, Franklin and Ffrench-Constant, 2008). Indeed, remyelination is the default response to demyelination occurring with great efficiency in not only experimental models of demyelination but also following demyelination associated with traumatic injury and in many MS lesions, especially those occurring early in the disease (Blakemore, 1973, Lasiene et al., 2008, Patani et al., 2007, Patrikios et al., 2006). Nevertheless, it is clear that in MS remyelination frequently fails leading to persistent demyelination and eventually axon degeneration (Patrikios et al., 2006). In this respect, there may be lessons learned from MS that can apply to other conditions. Periventricular leukomalacia (PVL), which primarily affects the brain of premature infants and can lead to cerebral palsy, also demonstrates failure of myelin repair (Billiards et al., 2008), which might result from and/or play a role in the subsequent development of axonal degeneration (Haynes et al., 2008).

How, therefore, might remyelination in MS and possibly other human myelin disorders be enhanced? One proposed approach that has attracted considerable attention is to bypass the endogenous process and transplant myelinogenic cells of which several types have been described. However, this approach presents a variety of obstacles, including how to achieve (1) the proper delivery and distribution of cells within a multifocal disease, (2) efficiency of repair within demyelinated environments that–as indicated above–do not support endogenous repair, and (3) generation of large numbers of cells that may require immunosuppressive protocols. For these and other reasons (reviewed previously (by Baron-Van Evercooren et al., 2004, Franklin and Ffrench-Constant, 2008) this strategy will not be further addressed here. An alternative approach is to identify ways of enhancing the endogenous remyelination process based on a precise and comprehensive knowledge of why remyelination fails.

The principal source of new remyelinating cells is an abundant and widespread population of cells in the adult CNS traditionally called oligodendrocyte precursor cells (OPCs). These cells are both self-renewing in the adult and can give rise to certain neurons in vivo, and so could reasonably be regarded as type of adult neural stem cell (however, changes in nomenclature often lag behind experimental evidence supporting these changes) (Nunes et al., 2003, Rivers et al., 2008, Zhu et al., 2008). For the purposes of this review we will use the term OPC to include NG2 cells. The innate immune response to demyelination causes OPCs to become activated, a morphological change accompanied by upregulation of genes not normally expressed in the resting state (Fancy et al., 2004, Glezer et al., 2006, Watanabe et al., 2004, Zhao et al., 2009). Activated OPCs divide and migrate and rapidly fill up the demyelinated lesions at a density that far exceeds that in normal tissue. To complete the remyelination process the cell must exit the cell cycle and differentiate into myelin sheath-forming oligodendrocytes, a complex process involving axon engagement, ensheathment and formation of compacted myelin (Chen et al., 2009, Crockett et al., 2005). As with all regenerative processes the efficiency of remyelination decreases with age, primarily due to a decrease in the ability of recruited cells to differentiate (Shields et al., 1999, Sim et al., 2002, Woodruff et al., 2004). This age-associated decline in remyelination mirrors and may be in part a determinant of a now well-recognised feature of many chronically demyelinated MS lesions that are replete with oligodendrocyte lineage cells that fail to differentiate into myelinating oligodendrocytes (Chang et al., 2002, Kuhlmann et al., 2008, Wolswijk, 1998).

Taken together both experimental and clinical-pathological studies point to the impairment of precursor differentiation as a key feature of inefficient or failed remyelination in MS. This means that identifying pathways involved in the regulation of OPC differentiation in myelination and especially remyelination that can potentially be manipulated pharmacologically represents a critical task in the development of new therapies for enhancing endogenous remyelination and thus axonal protection in MS and other myelin disorders. In this article we will review recent developments in the cell biology of precursor differentiation during remyelination and indicate how this knowledge may be translated into new drug-based therapies to overcome remyelination failure in MS and other myelin disorders. We focus on three signaling pathways—notch pathway (canonical and non-canonical), wnt pathway and pathways activated by myelin debris. Lingo-1 has also been implicated as a negative regulator of myelination (Mi et al., 2005) and, on the basis of pro-remyelination effects of Lingo-1 blocking antibodies, of remyelination (Mi et al., 2009). Since the therapeutic opportunities presented by Lingo-1 have been reviewed elsewhere (Rudick et al., 2008) we have not included a discussion of this topic in this review.