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抑制CLK2可改善与SHANK3缺乏相关的自闭症特征

Michael Bidinosti¹, Paolo Botta², Sebastian Krüttner²

¹Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland.

Science (New York, N.Y.)

|February 6, 2016

概括

与菲兰-麦克德米德综合症和自闭症相关的SHANK3缺乏, 破坏了大脑的信号传输. 准CLK2或激活Akt可以恢复神经元功能和社会行为,

科学领域:

神经科学
分子生物学
遗传学

背景情况:

这种SHANK3缺陷会导致费兰-麦克德米德综合征 (PMDS) 的神经特征,包括高自闭症谱系障碍 (ASD) 的风险.
了解SHANK3缺陷下游的分子机制对于开发向治疗至关重要.

研究的目的:

识别Shank3缺陷神经元的蛋白组中的分子变化.
阐明SHANK3缺乏影响的信号通路.
探索PMDS和相关ASD的潜在治疗点.

主要方法:

无偏见的定量蛋白质组学分析神经元的蛋白质组.
研究了蛋白质激酶B (PKB/Akt) 的作用,哺乳动物的目标是拉帕米辛复合物1 (mTORC1),血清蛋白/氨酸蛋白酸酶2A (PP2A) 和Cdc2类激酶2 (CLK2).
在细胞和动物模型中利用药理和基因操纵.

主要成果:

观察到Akt-mTORC1信号的下调.
由CLK2水平升高所导致的PP2A调节子单元B56β的增强酸化和激活被确定为关键机制.
在Shank3缺陷神经元和患者衍生的细胞中,Akt或CLK2抑制的药理/遗传激活改善了突触缺陷.
在Shank3缺陷的小鼠模型中,CLK2抑制恢复了社会行为.

结论:

SHANK3 缺乏导致通过 CLK2 介导的 PP2A 激活的 Akt- mTORC1 信号放松.
针对CLK2或激活Akt是一种有前途的治疗策略.
这项研究为SHANK3相关的神经发育障碍提供了新的机制见解.

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