Proteolipid protein gene expression in demyelination and remyelination of the central nervous system: a model for multiple sclerosis.
We asked whether nonlethal injury to the oligodendrocyte as manifested by altered myelin gene expression is an early event in the pathogenesis of demyelinating disease and subsequent remyelination. Using simultaneous in situ hybridization and immunocytochemistry, we studied expression of proteolipid protein (PLP) antigen and mRNA in spinal cords of normal adult mice and of mice infected with Theiler's virus which provides an excellent model for multiple sclerosis. Downregulation of PLP mRNA was observed within 3 days and persisted for as long as 367 days following intracerebral virus infection of SJL/J mice which are susceptible to chronic demyelination. Downregulation of myelin gene products preceded the development of prominent inflammation and demyelination observed following virus infection. In contrast, no change from control uninfected mice was observed in the expression of PLP mRNA following infection of C57BL/10SNJ mice which are resistant to demyelination. Treatment of chronically infected susceptible SJL/J mice with a regimen which promotes CNS-type (oligodendroglial) remyelination resulted in a 3- to 4-fold increase in PLP mRNA expression in oligodendrocytes. Actin mRNA expression in PLP antigen-positive cells was unchanged following TMEV-induced demyelination or remyelination indicating up- or downregulation of myelin gene products as compared to constitutively expressed actin gene. These experiments support the hypothesis that early regulation of myelin gene expression may be an important determinant in demyelination and in remyelination following nonlethal injury to oligodendrocytes.
Rodriguez
M
M
Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905.
Prayoonwiwat
N
N
Howe
C
C
Sanborn
K
K
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009185:Myelin Proteins / Q000032:analysis / Q000096:biosynthesis*; D018991:Myelin Proteolipid Protein; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology*; D011051:Poliomyelitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology*; D017945:Theilovirus; D013997:Time Factors
D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger