title: Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis.
abstract: Oligodendrocytes (OLs) fail to regenerate myelin destroyed by the immune attack in multiple sclerosis (MS) and lesion areas are eventually largely occupied by astrocytic scar tissue. Loss of OLs in MS does not account for the limited myelin repair as lesions contain a considerable number of OL precursor cells (OPC). Activation of the Notch pathway has been shown to provide inhibitory signals for OPC and to hamper their ability to produce myelin during CNS development. Here we show that gamma-secretase inhibition of Notch signaling within OL of CNS of SJL/J mice with experimental autoimmune encephalomyelitis (EAE) significantly enhanced clinical recovery and in the CNS, promoted remyelination and reduced axonal damage. Functional assays confirmed decreased Notch signaling in inhibitor-treated groups. Therefore, gamma-secretase inhibition led to an environment more conducive to myelin repair and axonal survival. Our results suggest that manipulation of the environment associated with Notch activation in the mature CNS provides a promising therapeutic target in MS.
authors.affiliation: Department of Neurology, Medical University of Lodz, 22, Kopcinskiego Street, Lodz, 90-153 Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Jurynczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Jurewicz
authors.forename: Bartosz
authors.initials: B
authors.lastname: Bielecki
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001369:Axons / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D002490:Central Nervous System / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis; D009186:Myelin Sheath; D009457:Neuroglia / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014945:Wound Healing
chemical_list: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D010450:Endopeptidases; D018398:Homeodomain Proteins; D010455:Peptides; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C432344:MW167; C509282:Bace1 protein, mouse