SCHWANN-CELLS AS TARGETS FOR NEUROTOXICANTS

Schwann cells subserve a variety of roles in the peripheral nervous sy stem (PNS), including ionic homeostasis, and protection and possible m etabolic support of axons. It is, however, the myelinating subtype of these glia which appear most sensitive to toxic insults. Myelinating S chwann cells must synthesize large amounts of myelin proteins (P-0 is the major myelin protein) and lipids (cholesterol is most prominent) w ithin 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 vulnerab ility for the mature myelin sheath. Fortunately, Schwann cells are hig hly plastic; they dedifferentiate to more primitive precursor cells fo llowing a demyelinating insult, but are able to redifferentiate and re myelinate axons during subsequent nerve regeneration. For study of suc h processes, a useful model system is exposure of developing rats to t he element tellurium; this produces a highly synchronous primary demye lination of PNS which is followed closely by rapid remyelination. Inte rpretation of the metabolic events involved is simplified by the nearl y 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. Particular ly useful have been studies of gene expression of certain proteins (ne rve growth factor receptor, myelin proteins, macrophage-specific lysoz yme) 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 N GF-R mRNA is a sensitive marker of nerve damage; it may be useful as a screen for potentially neurotoxic compounds. (C) 1996 Inter Press, In c.