Schwann cells as targets for neurotoxicants

Schwann cells subserve a variety of roles in the peripheral nervous system (PNS), including ionic homeostasis, and protection and possible metabolic support of axons. It is, however, the myelinating subtype of these glia which appear most sensitive to toxic insults. Myelinating Schwann cells must synthesize large amounts of myelin proteins (P0 is the major myelin protein) and lipids (cholesterol is most prominent) within a short, tightly-programmed developmental window. Schwann cells are preferentially vulnerable to neurotoxic insults during this period of maximal metabolic stress. The hydrophobicity of myelin (reservoir for lipid-soluble toxicants) and possible specialized energy-requiring mechanisms for maintenance of myelin structure are points of vulnerability for the mature myelin sheath. Fortunately, Schwann cells are highly plastic; they dedifferentiate to more primitive precursor cells following a demyelinating insult, but are able to redifferentiate and remyelinate axons during subsequent nerve regeneration. For study of such processes, a useful model system is exposure of developing rats to the element tellurium; this produces a highly synchronous primary demyelination of PNS which is followed closely by rapid remyelination. Interpretation of the metabolic events involved in simplified by the nearly complete lack of axonal degeneration. We have uncovered the primary lesion (block in cholesterol biosynthesis) and elucidated some of the steps involved in the demyelination-remyelination response. Particularly useful have been studies of gene expression of certain proteins (nerve growth factor receptor, myelin proteins, macrophage-specific lysozyme) which have enabled us to define some of the cellular responses to this toxicant-induced injury. A generally applicable result that has emerged from these and other similar studies is that upregulation of NGF-R mRNA is a sensitive marker of nerve damage; it may be useful as a screen for potentially neurotoxic compounds.