title: Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses.
abstract: Recent studies suggest that synaptic pathology in autism spectrum disorder (ASD) might be caused by the disruption of a signaling pathway at excitatory glutamatergic synapses, which can be influenced by environmental factors. Some factors, such as prenatal zinc deficiency, dysfunction of metallothioneins as well as deletion of COMMD1, all affect brain metal-ion homeostasis and have been associated with ASD. Given that COMMD1 regulates copper levels and that copper and zinc have antagonistic properties, here, we followed the idea that copper overload might induce a local zinc deficiency affecting key players of a putative ASD pathway such as ProSAP/Shank proteins as reported before. Our results show that increased copper levels indeed interfere with intracellular zinc concentrations and affect synaptic ProSAP/Shank levels, which similarly are altered by manipulation of copper and zinc levels through overexpression and knockdown of COMMD1. In line with this, acute and prenatal copper overload lead to local zinc deficiencies in mice. Pups exposed to prenatal copper overload furthermore show a reduction in ProSAP/Shank protein levels in the brain as well as a decreased NMDAR subunit 1 concentration. Thus, it might be likely that brain metal ion status influences a distinct pathway in excitatory synapses associated with genetic forms of ASD.
authors.affiliation: WG molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Baecker
authors.forename: Katharina
authors.initials: K
authors.lastname: Mangus
authors.forename: Stefanie
authors.initials: S
authors.lastname: Pfaender
authors.forename: Resham
authors.initials: R
authors.lastname: Chhabra
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003300:Copper / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis; D006801:Humans; D008431:Maternal-Fetal Exchange; D008809:Mice, Inbred C3H; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C103799:Commd1 protein, mouse; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C512412:SHANK1 protein, mouse; D003300:Copper; D015032:Zinc