title: Uncoupling Neogenin association with lipid rafts promotes neuronal survival and functional recovery after stroke.
abstract: The dependence receptor Neogenin and its ligand, the repulsive guidance molecule a (RGMa), regulate apoptosis and axonal growth in the developing and the adult central nervous system (CNS). Here, we show that this pathway has also a critical role in neuronal death following stroke, and that providing RGMa to neurons blocks Neogenin-induced death. Interestingly, the Neogenin pro-death function following ischemic insult depends on Neogenin association with lipid rafts. Thus, a peptide that prevents Neogenin association with lipid rafts increased neuronal survival in several in vitro stroke models. In rats, a pro-survival effect was also observed in a model of ocular ischemia, as well as after middle cerebral artery occlusion (MCAO). Treatments that prevented Neogenin association with lipid rafts improved neuronal survival and the complexity of the neuronal network following occlusion of the middle artery. Toward the development of a treatment for stroke, we developed a human anti-RGMa antibody that also prevents Neogenin association with lipid rafts. We show that this antibody also protected CNS tissue from ischemic damage and that its application resulted in a significant functional improvement even when administrated 6 h after artery occlusion. Thus, our results draw attention to the role of Neogenin and lipid rafts as potential targets following stroke.
authors.affiliation: 1] Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada [2] Department of Anatomy, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: A P
authors.initials: AP
authors.lastname: Shabanzadeh
authors.affiliation: 1] Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada [2] Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: N G
authors.initials: NG
authors.lastname: Tassew
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Szydlowska
authors.affiliation: 1] Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada [2] Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada [3] Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Tymianski
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: 1] Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada [2] Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: R J
authors.initials: RJ
authors.lastname: Vigouroux
authors.affiliation: 1] Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada [2] Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: J H
authors.initials: JH
authors.lastname: Eubanks
authors.affiliation: AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: Neuroscience Research, Research and Development, AbbVie Deutschland GmbH & CO KG, Knollstrasse, D-67061 Ludwigshafen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Geraerts
authors.affiliation: 1] Department of Anatomy, Faculty of Medicine, University of Toronto, Toronto, ON, Canada [2] Department of Ophthalmology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: P D
authors.initials: PD
authors.lastname: Koeberle
authors.affiliation: Neuroscience Research, Research and Development, AbbVie Deutschland GmbH & CO KG, Knollstrasse, D-67061 Ludwigshafen, Germany.
authors.forename: B K
authors.initials: BK
authors.lastname: Mueller
authors.affiliation: 1] Toronto Western Research Institute, Genetics and Development Division, KDT 8-418, 60 Leonard Street, Toronto, M5T 2S8 ON, Canada [2] Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada [3] Department of Ophthalmology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: P P
authors.initials: PP
authors.lastname: Monnier
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D002470:Cell Survival / Q000502:physiology; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000276:immunology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020521:Stroke / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C522183:RGMA protein, human; C483496:Rgma protein, mouse; C091279:neogenin