No abstract

Axonal degeneration determines the clinical outcome of multiple sclerosis (MS), and is thought to result from exposure of denuded axons to immune-mediated damage. We challenge this view after finding in MS and its mouse models that myelin itself increases the risk of axons to degenerate under inflammatory conditions. We propose a model for demyelinating diseases in which for axons that remain myelinated, and thus shielded from the extracellular milieu, dependence from oligodendroglial support turns fatal in an autoimmune disease environment.

The two proteins, proteolipid protein and DM20, which are encoded by alternative transcripts from the proteolipid protein (PLP) gene, are major components of central nervous system myelin. In man, mutations of these proteins cause Pelizaeus‐Merzbacher disease (PMD), an X‐linked dysmyelinating neuropathy. The mutations found are very varied, ranging from deletions, loss‐of‐function and missense mutations to additional copies of the gene. This same range of known genetic defects has been observed in animal models with spontaneous and engineered Pip gene mutations. The relationship between genotype and phenotype is remarkably close in the animal models and the PMD cases, making them useful models for studying the mechanisms of PLP gene‐related disease. As a result, it has become clear that the PLP gene plays a wider role in neural development in addition to its function as a structural component of myelin. It has also emerged that duplications of the PLP gene are the commonest mutation in PMD. Genetic disorders arising from a dosage effect may be more common than previously recognized. The study of the PLP gene in this rare disorder is, therefore, contributing both to our understanding of neural development and maintenance and to the mechanisms of human genetic disorders.