Neuronal Copper Homeostasis Susceptibility by Genetic Defects in Dysbindin, a Schizophrenia Susceptibility Factor
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Human Molecular Genetics
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.
Gokhale, Avanti; Vrailas-Mortimer, Alysia; Larimore, Jennifer; Comstra, Heather; Zlatic, Stephanie; Werner, Erica; Manvich, Daniel; Iuvone, P.; Weinshenker, David; and Faundez, Victor, "Neuronal Copper Homeostasis Susceptibility by Genetic Defects in Dysbindin, a Schizophrenia Susceptibility Factor" (2015). School of Osteopathic Medicine Faculty Scholarship. 29.
Gokhale A, Vrailas-Mortimer A, Larimore J, Comstra HS, Zlatic SA, Werner E, Manvich DF, Iuvone PM, Weinshenker D, Faundez V. Neuronal copper homeostasis susceptibility by genetic defects in dysbindin, a schizophrenia susceptibility factor. Hum Mol Genet. 2015 Oct 1;24(19):5512-23. Epub 2015 Jul 21. doi: 10.1093/hmg/ddv282. PMID: 26199316. PMCID: PMC4572075.