title: Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior.
abstract: The biological underpinnings and the pathological lesions of psychiatric disorders are centuries-old questions that have yet to be understood. Recent studies suggest that schizophrenia and related disorders likely have their origins in perturbed neurodevelopment and can result from a large number of common genetic variants or multiple, individually rare genetic alterations. It is thus conceivable that key neurodevelopmental pathways underline the various genetic changes and the still unknown pathological lesions in schizophrenia. Here, we report that mice defective of the nicastrin subunit of γ-secretase in oligodendrocytes have hypomyelination in the central nervous system. These mice have altered dopamine signaling and display profound abnormal phenotypes reminiscent of schizophrenia. In addition, we identify an association of the nicastrin gene with a human schizophrenia cohort. These observations implicate γ-secretase and its mediated neurodevelopmental pathways in schizophrenia and provide support for the "myelination hypothesis" of the disease. Moreover, by showing that schizophrenia and obsessive-compulsive symptoms could be modeled in animals wherein a single genetic factor is altered, our work provides a biological basis that schizophrenia with obsessive-compulsive disorder is a distinct subtype of schizophrenia.
authors.affiliation: From the Departments of Neuroscience, the Chemistry Department, Juniata College, Huntingdon, Pennsylvania 16652.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Dries
authors.affiliation: From the Departments of Neuroscience.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: From the Departments of Neuroscience.
authors.forename: Mieu M
authors.initials: MM
authors.lastname: Brooks
authors.affiliation: the Laboratory of NeuroPsychiatric Genetics, Biomedical Sciences Research Group, School of Medicine, Universidad Antonio Nariño, 37-94 Bogotá, Colombia.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Forero
authors.affiliation: Psychiatry, and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Adachi
authors.affiliation: From the Departments of Neuroscience.
authors.forename: Basar
authors.initials: B
authors.lastname: Cenik
authors.affiliation: From the Departments of Neuroscience.
authors.forename: James M
authors.initials: JM
authors.lastname: West
authors.affiliation: From the Departments of Neuroscience.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Han
authors.affiliation: From the Departments of Neuroscience.
authors.forename: Cong
authors.initials: C
authors.lastname: Yu
authors.affiliation: the Chemistry Department, Juniata College, Huntingdon, Pennsylvania 16652.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Arbella
authors.affiliation: the Division of Psychiatry, Department of Clinical Sciences, Umea University, SE-901 87 Umea, Sweden.
authors.forename: Annelie
authors.initials: A
authors.lastname: Nordin
authors.affiliation: the Division of Psychiatry, Department of Clinical Sciences, Umea University, SE-901 87 Umea, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Adolfsson
authors.affiliation: the Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Del-Favero
authors.affiliation: the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, and Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
authors.affiliation: the Laboratory of Behavioral and Developmental Genetics, Katholieke Universiteit Leuven Center for Human Genetics, VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Callaerts
authors.affiliation: Psychiatry, and.
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.affiliation: From the Departments of Neuroscience, gang.yu@utsouthwestern.edu.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003192:Compulsive Behavior; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer disease; gamma-secretase; gene knockout; hypomyelination; myelin; nicastrin; obsessive-compulsive disorder; oligodendrocyte; schizophrenia; white matter