title: Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult.
abstract: Multiple sclerosis is a chronic inflammatory disease of the CNS leading to focal destruction of myelin, still the earliest changes that lead to lesion formation are not known. We have studied the gene-expression pattern of 12 samples of normal appearing white matter from 10 post-mortem MS brains. Microarray analysis revealed upregulation of genes involved in maintenance of cellular homeostasis, and in neural protective mechanisms known to be induced upon ischemic preconditioning. This is best illustrated by the upregulation of the transcription factors such as HIF-1alpha and associated PI3K/Akt signalling pathways, as well as the upregulation of their target genes such as VEGF receptor 1. In addition, a general neuroprotective reaction against oxidative stress is suggested. These molecular changes might reflect an adaptation of cells to the chronic progressive pathophysiology of MS. Alternatively, they might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS. Our data introduce novel concepts of the molecular pathogenesis of MS with ischemic preconditioning as a major mechanism for neuroprotection. An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligondendrocyte and axonal loss.
authors.affiliation: Department of Research and Neurology, University Hospital Basel, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Graumann
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Steck
authors.forename: Nicole
authors.initials: N
authors.lastname: Schaeren-Wiemers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D064127:Aurora Kinases; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D064127:Aurora Kinases; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009687:Nuclear Proteins; D010396:Penicillamine; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D014157:Transcription Factors; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497442:HIF1A protein, human; C571326:MOG protein, human; C078341:MYT1 protein, human; C571327:Mog protein, mouse; C489726:Myt1 protein, mouse; C110881:S-nitro-N-acetylpenicillamine