CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency
CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency
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DOI：
10.1126/science.aad5487
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发表时间：
2016-03-11
期刊：
影响因子：
56.9
通讯作者：
Galimberti, Ivan
中科院分区：
文献类型：
--
作者：
Bidinosti, Michael;Botta, Paolo;Galimberti, Ivan
SH 3和多个锚蛋白重复结构域3（SHANK 3）单倍不足是导致包括自闭症谱系障碍（ASD）的高风险在内的M-M综合征（PMDS）的神经学特征的原因。我们使用无偏的定量蛋白质组学来鉴定Shank 3缺陷神经元磷酸化蛋白质组的变化。蛋白激酶B（PKB/Akt）-哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）信号转导的下调是由于丝氨酸/苏氨酸蛋白磷酸酶2A（PP 2A）调节亚基B56 B的磷酸化和活化增强所致，这是由于其激酶Cdc 2样激酶2（CLK 2）的稳态水平增加所致。Akt的药理和遗传激活或CLK 2的抑制缓解了Shank 3缺陷和PMDS患者源性神经元的突触缺陷。在Shank 3缺陷小鼠模型中，CLK 2抑制也恢复了正常的社交能力。因此，我们的研究提供了一个新的机制和潜在的治疗理解失调信号下游的Shank 3缺陷。
SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56b, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.