The axons that carry nerve impulses between neurons must be sheathed in myelin if they are to function. This structured myelin is built and maintained by a specialized population of cells called oligodendrocytes, which derive from a precursor population. Loss of myelin is a feature of severely disabling and ultimately fatal conditions such as multiple sclerosis. To a lesser degree, however, myelin loss also takes place with advancing age, and evidence suggests that this contributes to cognitive decline at the very least. Anything that disrupts the activity of oligodendrocytes will lead to loss of myelin, and the underlying damage that drives aging disrupts all cell populations in a variety of ways, to an increasing degree as the burden of damage rises over time.
The connection with aging is why it is worth keeping an eye on progress towards the development of therapies for multiple sclerosis. Therapies that treat demyelinating conditions may turn out be useful in older people as well. The details do matter, however. The targeted mechanisms must be applicable in both disease and aging, and it isn’t always clear that this is the case. Today’s open access paper is an example in which the researchers focus on multiple sclerosis patients and animal models of demyelination that have no relevance to aging. Thus the target they uncover does seem promising, but may or may not turn out to be useful outside the scope of multiple sclerosis.
Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination.
We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination in vivo.
This data indicates that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.
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