Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination.
Exposure of mice to the copper chelator, cuprizone, results in CNS demyelination. There is remyelination after removal of the metabolic insult. We present brain regional studies identifying corpus callosum as particularly severely affected; 65% of cerebroside is lost after 6 weeks of exposure. We examined recovery of cerebroside and ability to synthesize cerebroside and cholesterol following removal of the toxicant. The temporal pattern for concentration of myelin basic protein resembled that of cerebroside. We applied Affymetrix GeneChip technology to corpus callosum to identify temporal changes in levels of mRNAs during demyelination and remyelination. Genes coding for myelin structural components were greatly down-regulated during demyelination and up-regulated during remyelination. Genes related to microglia/macrophages appeared in a time-course (peaking at 6 weeks) correlating with phagocytosis of myelin and repair of lesions. mRNAs coding for many cytokines had peak expression at 4 weeks, compatible with intercellular signaling roles. Of interest were other genes with temporal patterns correlating with one of the three above patterns, but of function not obviously related to demyelination/remyelination. The ability to correlate gene expression with known pathophysiological events should help in elucidating further function of such genes as related to demyelination/remyelination.
Jurevics
Helga
H
Neuroscience Center, Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599-7250, USA.
Largent
Carrie
C
Hostettler
Janell
J
Sammond
Deanne W
DW
Matsushima
Glenn K
GK
Kleindienst
Amber
A
Toews
Arrel D
AD
Morell
Pierre
P
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000737:chemistry / Q000378:metabolism; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D002554:Cerebrosides / Q000032:analysis / Q000378:metabolism; D002614:Chelating Agents; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism; D003337:Corpus Callosum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005700:Galactosyltransferases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D004676:Myelin Basic Protein / Q000032:analysis / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D051146:N-Acylsphingosine Galactosyltransferase; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
D015415:Biomarkers; D002554:Cerebrosides; D002614:Chelating Agents; D004676:Myelin Basic Protein; D012333:RNA, Messenger; D003471:Cuprizone; D002784:Cholesterol; D005700:Galactosyltransferases; D051146:N-Acylsphingosine Galactosyltransferase