Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses
Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses
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DOI：
10.1007/s10534-014-9764-1
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发表时间：
2014-08-01
期刊：
影响因子：
3.5
通讯作者：
Grabrucker, Andreas M.
中科院分区：
文献类型：
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作者：
Baecker, Tanja;Mangus, Katharina;Grabrucker, Andreas M.
最近的研究表明，自闭症谱系障碍（ASD）中的突触病理可能是由兴奋性突触的信号通路中断引起的，这可能受到环境因素的影响。一些因素，如产前锌缺乏，金属硫蛋白功能障碍以及COMMD 1的缺失，都影响脑金属离子稳态，并已与ASD。考虑到COMMD 1调节铜水平，并且铜和锌具有拮抗特性，在这里，我们遵循这样的想法，即铜过载可能会诱导局部锌缺乏，影响推定的ASD途径的关键参与者，如之前报道的ProSAP/Shank蛋白。我们的研究结果表明，增加铜水平确实干扰细胞内锌浓度，并影响突触ProSAP/柄水平，这同样是通过操纵铜和锌水平，通过过表达和敲低COMMD 1改变。与此一致，急性和产前铜超载导致小鼠局部锌缺乏。此外，暴露于产前铜过载的幼崽显示脑中ProSAP/Shank蛋白水平降低以及NMDAR亚基1浓度降低。因此，可能是脑金属离子状态影响与遗传形式的ASD相关的兴奋性突触中的独特途径。
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.