Table_1_Mutations in the postsynaptic density signaling hub TNIK disrupt PSD signaling in human models of neurodevelopmental disorders.xlsx

A large number of synaptic proteins have been recurrently associated with complex brain disorders. One of these proteins, the Traf and Nck interacting kinase (TNIK), is a postsynaptic density (PSD) signaling hub, with many variants reported in neurodevelopmental disorder (NDD) and psychiatric disease. While rodent models of TNIK dysfunction have abnormal spontaneous synaptic activity and cognitive impairment, the role of mutations found in patients with TNIK protein deficiency and TNIK protein kinase activity during early stages of neuronal and synapse development has not been characterized. Here, using hiPSC-derived excitatory neurons, we show that TNIK mutations dysregulate neuronal activity in human immature synapses. Moreover, the lack of TNIK protein kinase activity impairs MAPK signaling and protein phosphorylation in structural components of the PSD. We show that the TNIK interactome is enriched in NDD risk factors and TNIK lack of function disrupts signaling networks and protein interactors associated with NDD that only partially overlap to mature mouse synapses, suggesting a differential role of TNIK in immature synapsis in NDD.

大量突触蛋白已被反复证实与复杂脑疾病密切相关。其中一类蛋白为Traf与Nck相互作用激酶（Traf and Nck interacting kinase, TNIK），其作为突触后致密区（postsynaptic density, PSD）信号枢纽，目前已在神经发育障碍（neurodevelopmental disorder, NDD）与精神疾病中报道了多种该蛋白的变异体。尽管TNIK功能异常的啮齿类动物模型可出现自发性突触活动异常与认知障碍，但患者体内检出的TNIK蛋白缺陷突变，以及TNIK蛋白激酶活性在神经元与突触发育早期阶段的具体作用，迄今仍未得到明确表征。本研究借助诱导多能干细胞（human induced pluripotent stem cells, hiPSC）分化获得的兴奋性神经元，证实TNIK突变会在人类未成熟突触中异常调控神经元活动。此外，TNIK蛋白激酶活性的缺失会损害突触后致密区结构组分中的丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）信号通路与蛋白质磷酸化过程。研究表明，TNIK相互作用组富含神经发育障碍风险因子；且TNIK功能缺失会破坏与神经发育障碍相关的信号网络及蛋白互作因子，这类关联仅与成熟小鼠突触存在部分重叠，这提示TNIK在神经发育障碍相关的未成熟突触中发挥差异化的调控作用。