title: Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor.
abstract: Environmental factors and susceptible genomes interact to determine the risk of neurodevelopmental disorders. Although few genes and environmental factors have been linked, the intervening cellular and molecular mechanisms connecting a disorder susceptibility gene with environmental factors remain mostly unexplored. Here we focus on the schizophrenia susceptibility gene DTNBP1 and its product dysbindin, a subunit of the BLOC-1 complex, and describe a neuronal pathway modulating copper metabolism via ATP7A. Mutations in ATP7A result in Menkes disease, a disorder of copper metabolism. Dysbindin/BLOC-1 and ATP7A genetically and biochemically interact. Furthermore, disruption of this pathway causes alteration in the transcriptional profile of copper-regulatory and dependent factors in the hippocampus of dysbindin/BLOC-1-null mice. Dysbindin/BLOC-1 loss-of-function alleles do not affect cell and tissue copper content, yet they alter the susceptibility to toxic copper challenges in both mammalian cells and Drosophila. Our results demonstrate that perturbations downstream of the schizophrenia susceptibility gene DTNBP1 confer susceptibility to copper, a metal that in excess is a neurotoxin and whose depletion constitutes a micronutrient deficiency.
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Avanti
authors.initials: A
authors.lastname: Gokhale
authors.affiliation: Department of Biological Sciences, University of Denver, Denver, CO 80208, USA and.
authors.forename: Alysia
authors.initials: A
authors.lastname: Vrailas-Mortimer
authors.affiliation: Department of Biology, Agnes Scott College, Decatur, GA 30030, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Larimore
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Comstra
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Zlatic
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Werner
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Manvich
authors.affiliation: Department of Ophthalmology, Emory University, Atlanta, GA 30322, USA.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Iuvone
authors.affiliation: Department of Human Genetics, Emory University, Atlanta, GA 30322, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.affiliation: Department of Cell Biology, Emory University, Atlanta, GA 30322, USA, Center for Social Translational Neuroscience, Emory University, Atlanta, GA 30322, USA, vfaunde@emory.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics*
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D029721:Drosophila Proteins; C498992:Dtnbp1 protein, mouse; C569104:Dysb protein, Drosophila; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases