Oligodendrocytes, Myelin and Multiple Sclerosis

A leading cause of adult neurologic disability in the western world, multiple sclerosis (MS) is an autoimmune disorder of unclear etiology that results in chronic, inflammatory, multifocal demyelination of the central nervous system (CNS). The heterogeneous course of MS starts with an early inflammatory relapsing-remitting phase, before progressing into a degenerative stage associated with scar formation and axon loss. Oligodendrocytes are the principal cells involved in CNS myelination and therefore become prime pathological targets in MS. In early MS, oligo-dendropathies are thought to be caused primarily by B cell and T lymphocyte-mediated attack on neuronal antigens whilst axonal degeneration in the later stages of MS is thought to be induced by intraxonal Ca2+ overload due to compensatory redistribution of Na+ channels. Thus, although axonal loss and degenerative processes occur early in the disease process, it is only later when compensatory strategies fail that the signs of clinical progression in MS become evident. At present, anti-inflammatory therapies have shown poor efficacy in late MS, suggesting that mechanisms independent of inflammation may be responsible for the continued axonal degeneration in chronic MS. Current research investigating alternative therapies have considered blockade of Na+ channels to reduce Ca2+ toxicity and increasing expression of neuroprotective growth factors. Whilst preliminary trial data have identified LINGO-1 as a negative regulator of myelination and oligodendrocyte precursor cell differentiation, use of anti-LINGO-1 in a phase II clinical trial has shown disappointing results. On the other hand, sphingosine-1-phosphate receptor modulators, anti-CD20 B cell and anti-alpha-4 integrin antibody therapies have demonstrated promising efficacy profiles in clinical trials. Despite varied results, further research into the mechanisms of axonal injury and their clinical relevance in MS is still recommended in order to develop successful, targeted neuroprotective therapies in the future.