Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders
Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders
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DOI：
10.1093/brain/awt303
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发表时间：
2014-01-01
期刊：
影响因子：
14.5
通讯作者：
Grabrucker, Andreas M.
中科院分区：
文献类型：
--
作者：
Grabrucker, Stefanie;Jannetti, Linda;Grabrucker, Andreas M.
ProSAP/Shank家族蛋白在兴奋性突触的突触后密度中起主要组织支架元件的作用。这些分子的缺失、突变或下调与自闭症谱系障碍、相关的费伦·麦克德米综合征或阿尔茨海默病有关。ProSAP/Shank蛋白依赖于与锌的结合而靶向突触，这是ProSAP/Shank支架组装的先决条件。为了深入了解之前报道的ProSAP/Shank通过锌离子的组装是否提供了自闭症谱系障碍遗传形式和锌缺乏作为自闭症谱系障碍环境风险因素之间的交叉点，我们使用神经生物学方法在体外和体内研究了锌和ProSAP/Shank之间的相互作用。我们的数据表明，低突触后锌可用性影响突触中ProSAP1/Shank2和ProSAP2/Shank3水平的活性依赖性增加，并且在急性和产前缺锌的小鼠模型中，突触中ProSAP1/Shank2和ProSAP2/Shank3的缺失发生。锌缺乏的动物表现出行为异常，如过度反应和多动样行为（急性锌缺乏），以及与自闭症谱系障碍相关的行为，如发声和社交行为障碍（产前锌缺乏）。最重要的是，低锌状态似乎与Phelan-McDermid综合征患者癫痫发作、张力低下、注意力和多动问题的发生率增加有关，这是由ProSAP2/Shank3单倍不足引起的。我们认为产前锌缺乏作为自闭症谱系障碍风险因素的分子基础可能通过锌结合ProSAP/Shank家族成员的解除调控而展开。
Proteins of the ProSAP/Shank family act as major organizing scaffolding elements within the postsynaptic density of excitatory synapses. Deletions, mutations or the downregulation of these molecules has been linked to autism spectrum disorders, the related Phelan McDermid Syndrome or Alzheimer's disease. ProSAP/Shank proteins are targeted to synapses depending on binding to zinc, which is a prerequisite for the assembly of the ProSAP/Shank scaffold. To gain insight into whether the previously reported assembly of ProSAP/Shank through zinc ions provides a crossing point between genetic forms of autism spectrum disorder and zinc deficiency as an environmental risk factor for autism spectrum disorder, we examined the interplay between zinc and ProSAP/Shank in vitro and in vivo using neurobiological approaches. Our data show that low postsynaptic zinc availability affects the activity dependent increase in ProSAP1/Shank2 and ProSAP2/Shank3 levels at the synapse in vitro and that a loss of synaptic ProSAP1/Shank2 and ProSAP2/Shank3 occurs in a mouse model for acute and prenatal zinc deficiency. Zinc-deficient animals displayed abnormalities in behaviour such as over-responsivity and hyperactivity-like behaviour (acute zinc deficiency) and autism spectrum disorder-related behaviour such as impairments in vocalization and social behaviour (prenatal zinc deficiency). Most importantly, a low zinc status seems to be associated with an increased incidence rate of seizures, hypotonia, and attention and hyperactivity issues in patients with Phelan-McDermid syndrome, which is caused by haploinsufficiency of ProSAP2/Shank3. We suggest that the molecular underpinning of prenatal zinc deficiency as a risk factor for autism spectrum disorder may unfold through the deregulation of zinc-binding ProSAP/Shank family members.