Tellurium-induced neuropathy: a model for reversible reductions in myelin protein gene expression.
Inclusion of 1.1% tellurium in the diet of developing rats causes a highly synchronous primary demyelination of peripheral nerves, which is followed closely by a period of rapid remyelination. The demyelination is related to the inhibition of squalene epoxidase activity, which results in a block in cholesterol synthesis and accumulation of squalene. We now report that the demyelination resulting from this limiting of the supply of an intrinsic component of myelin (cholesterol) leads to repression of the expression of mRNA for myelin-specific proteins. Tellurium exposure resulted in an increase in total RNA (largely rRNA) in sciatic nerve, which could not be accounted for by cellular proliferation; these increased levels of rRNA may be a reactive response of Schwann cells to toxic insult and may relate to the higher levels of protein synthesis required during remyelination. In contrast, steady-state levels of mRNA, determined by Northern blot analysis, for P0 and myelin basic protein were markedly decreased (levels after 5 days of tellurium exposure were only 10-15% of control levels as a fraction of total RNA and 25-35% of control levels when the increased levels of total RNA were taken into account). Message levels increased during the subsequent period of remyelination and reached near-normal levels 30 days after beginning tellurium exposure. Although message levels for the myelin-associated glycoprotein showed a similar temporal pattern, levels did not decrease as greatly and subsequently increased sooner than did levels for P0 and myelin basic protein. The coordinate alterations in message levels for myelin proteins indicate that Schwann cells can down-regulate and then up-regulate the synthesis of myelin in response to alterations in the supply of membrane components.
Toews
A D
AD
Department of Biochemistry, University of North Carolina, Chapel Hill 27599.
Lee
S Y
SY
Popko
B
B
Morell
P
P
D000818:Animals; D015152:Blotting, Northern; D004032:Diet; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D004676:Myelin Basic Protein / Q000096:biosynthesis; D009185:Myelin Proteins / Q000096:biosynthesis*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism; D013691:Tellurium / Q000633:toxicity*
D004676:Myelin Basic Protein; D009185:Myelin Proteins; D012333:RNA, Messenger; D013691:Tellurium