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Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses

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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.

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Acknowledgments

AMG is supported by Baustein 3.2 (L.SBN.0083) and the DAAD. SP and RC are members of the international graduate school in molecular medicine of Ulm University.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. WG molecular Analysis of Synaptopathies, Neurology Department, Neurocenter of Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    Tanja Baecker, Katharina Mangus, Resham Chhabra & Andreas M. Grabrucker

  2. Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, Ulm, Germany

    Stefanie Pfaender, Tobias M. Boeckers & Andreas M. Grabrucker

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  1. Tanja Baecker
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  2. Katharina Mangus
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  3. Stefanie Pfaender
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  4. Resham Chhabra
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  5. Tobias M. Boeckers
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  6. Andreas M. Grabrucker
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Corresponding author

Correspondence to Andreas M. Grabrucker.

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Fig. S1

a NIH cells were treated for 1 h with 10 μM ZnCl2, 10 μM CuCl2 or 10 μM ZnCl2 and 10 μM CuCl2. The intracellular Zn2+ levels were detected by quantification of the signal intensity values of Zinquin. Similar to neurons, a significant increase in intracellular Zn2+ levels can be seen under supplementation with Zn2+ that is inhibited by the application of Cu2+ together with Zn2+. b, c Treatment of hippocampal neurons at 14 DIV for 1 h with 10 μM ZnCl2, 10 μM CuCl2 or 10 μM ZnCl2 and 10 μM CuCl2 does not significantly alter dendritic branching (b) nor causes significant cell death (c) given that the number of nuclei (DAPI positive) did not change after treatment. Additionally, the number of apoptotic nuclei (fractioned nuclei) was not altered (data not shown)

Fig. S2

a HEK293 cells were transfected with either GFP-COMMD1 or MYC-COMMD1 and the overexpressed protein purified using magnetic GFP-beads or Myc-beads, respectively. Western Blot analysis shows that both, the GFP- and Myc-tagged fusion proteins of COMMD1 can be detected by anti GFP and anti Myc antibodies. Similarly, both anti COMMD1 antibodies used in this study (from Santa Cruz and Sigma Aldrich) are able to specifically label the COMMD1 fusion-proteins. b Protein lysate from untransfected NIH 3T3 cells (Control) as well as MYC-COMMD1, MYC-COMMD1 plus COMMD1 shRNA, or COMMD1 shRNA transfected cells was analyzed by Western Blot. The results show the average signal intensity of three lanes per group normalized against GAPDH. A significant knockdown effect of the shRNA plasmid can be seen. c Left panel: Transfection of COMMD1 shRNA for 3 days results in reduced anti-COMMD1 labeling in shRNA expressing (GFP positive (full arrow)) cells compared to an untransfected cell (open arrow). Anti-COMMD1 signals were imaged with same exposure time. Right panel Endogenous COMMD1 shows enrichment towards post-synapses labeled by ProSAP2/Shank3. d Overexpression or knockdown of COMMD1 by transfection of GFP-COMMD1 and COMMD1 shRNA encoding plasmids, respectively, does not alter synaptic ProSAP1/Shank2 or ProSAP2/Shank3 levels in hippocampal neurons without treatment with CuCl2 and ZnCl2. For the quantification, a puncta by puncta analysis of fluorescence intensities of immunoreactive signals was performed on 5–10 cells per group after 3 days of transfection at DIV 14. The values are shown in percent normalized to the respective controls (GFP expression (GFP Ctrl) and scrambled (scr) shRNA (scr-shRNA Ctrl)). For each cell, the ratio between the fluorescence intensity of the transfected cell and a neighboring untransfected cell was calculated. e Western Blot analysis of protein homogenate from Cortex (CTX), Striatum (STR), Hippocampus (HIP) and Cerebellum (CER) of wild type mice of two different time points (32 days and 18 months of age) reveals expression of COMMD1 in all aforementioned brain regions

Fig. S3

a Mice on a Cu2+- supplemented diet for 5 weeks show an increase in body weight after 21–25 days of treatment compared to control animals fed a normal diet. However, after 5 weeks both, supplemented and control mice had on average similar weights. b During the fifth week of treatment, mice fed a Cu2+—supplemented diet consumed more food compared to control animals. However, averaging over the whole time of treatment, no significant difference in food consumption was visible. c Mice on a Cu2+—supplemented diet for 5 weeks show a significant decrease in brain weight and an increase in the ratio of body/brain weight. d Analysis of cell density by DAPI staining of nuclei in the two brain regions (Hippocampus and Cortex) reveals a clear trend towards a decrease (p = 0.053, n = 3) in Cortex. e Using Nissl staining, sections from wt and Cu2+—supplemented mice (n = 3) we evaluated for cell density. Red boxes indicate optic fields measured within the sections (220 × 220 pixels). While no changes could be detected in Hippocampus, a significant reduction of cell density was observed in Cortex

Fig. S4

a, b ICP-MS analysis shows that animals fed a Cu2+ enriched diet contain on average a significantly higher amount of Cu2+ in their urine (a) and feces (b). b Zn2+ levels were slightly increased in feces of mice fed a Cu2+ enriched diet (p = 0.18; n = 3). c Analysis of Zn2+ concentrations in liver and kidney from three different animals per group using AAS indicates slightly reduced Zn2+ concentrations in blood and liver and a significantly reduced Zn2+ concentration in kidneys of animals fed a Cu2+—supplemented diet. d, e Analysis of Cu2+ and Zn2+ concentrations using ICP-MS from three animals per group shows no difference in average brain Cu2+ levels (d). e Average brain Zn2+ levels were significantly reduced in animals fed a Cu2+—supplemented diet. f Hippocampal brain sections treated with 15 μM TPEN for 10 min before Zinpyr-1 staining (upper panel) show almost no detectable fluorescence compared to untreated sections (lower panel). g Brain region specific analysis of Zn2+ (using Zinpyr-1) using at least three optic field of view per brain region from three different animals shows a significant reduction in Zinpyr-1 staining correlating with Zn2+ concentrations in Hippocampus. h Similarly to g brain region specific analysis of Zn2+ (using Timm stained puncta within on optic field from different brain regions) from three different animals shows a significant reduction of staining intensity in the Hippocampus

Fig. S5

a Whole brain mRNA levels were analyzed using qRT-PCR from three control and three Cu2+ supplemented mice. mRNA expression levels were normalized against HMBS. No significant changes in the expression level of metallothioneins (MT-1, MT-2, MT-3), MTF1 or the three ProSAP/Shank family members were detected. b Western Blot analysis of P2 fractions from whole brain lysate using control animals and Cu2+ supplemented mice (n = 3). No significant differences can be detected in ProSAP/Shank proteins or MTF-1, MT-3 and COMMD1. c Western Blot analysis of ProSAP/Shank proteins (left panel) in P2 fractions from different brain regions using control animals and Cu2+ supplemented mice (n = 3 pooled, 3 technical replicates). The results show a trend towards a decrease especially in hippocampus, however, no significant changes could be detected. Analysis of MTF1, COMMD1 and MT-3 (right panel) similarly revealed no significant alterations. d Sections of three animals from control and Cu2+ supplemented mice were stained for ProSAP1/Shank2, ProSAP2/Shank3 and Shank1. The signal intensity of synaptic ProSAP/Shank puncta was evaluated. A slight but significant decrease can be seen for ProSAP2/Shank3 in the hippocampus. Upper panels show exemplary sections for ProSAP2/Shank3. e The average signal density (all ProSAP/Shanks combined) per optic field was determined from sections of three animals per group. No significant changes in excitatory synapse density were detected

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Baecker, T., Mangus, K., Pfaender, S. et al. Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses. Biometals 27, 715–730 (2014). https://doi.org/10.1007/s10534-014-9764-1

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