title: Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits.
abstract: Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: S V
authors.initials: SV
authors.lastname: Trossbach
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Bader
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Hecher
authors.affiliation: Center for Behavioral Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: M E
authors.initials: ME
authors.lastname: Pum
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S T
authors.initials: ST
authors.lastname: Masoud
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Prikulis
authors.affiliation: Center for Behavioral Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schäble
authors.affiliation: Center for Behavioral Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: de Souza Silva
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Su
authors.affiliation: Functional Architecture of Memory Unit, Mercator Research Group, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Boulat
authors.affiliation: Functional Architecture of Memory Unit, Mercator Research Group, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Chwiesko
authors.affiliation: Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Poschmann
authors.affiliation: Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stühler
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Lohr
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: K A
authors.initials: KA
authors.lastname: Stout
authors.affiliation: Institute of Neuroscience and Medicine, INM-2, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Oskamp
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: S F
authors.initials: SF
authors.lastname: Godsave
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Müller-Schiffmann
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bilzer
authors.affiliation: Department of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Steiner
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Peters
authors.affiliation: Institute of Neuroscience and Medicine, INM-2, Forschungszentrum Jülich, Jülich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Functional Architecture of Memory Unit, Mercator Research Group, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Sauvage
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Ramsey
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Miller
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.affiliation: Departments of Pharmacology and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Seeman
authors.affiliation: AstraZeneca Neuroscience iMED, Cambridge, MA, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Center for Behavioral Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: J P
authors.initials: JP
authors.lastname: Huston
authors.affiliation: Department Neuropathology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Korth
mesh_terms: D000661:Amphetamine; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: C412476:DISC1 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D004298:Dopamine