Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease
Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease
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DOI：
10.1016/j.celrep.2019.08.104
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发表时间：
2019-10-08
期刊：
影响因子：
8.8
通讯作者：
Shulman, Joshua M.
中科院分区：
文献类型：
--
作者：
Hsieh, Yi-Chen;Guo, Caiwei;Shulman, Joshua M.
在阿尔茨海默病（AD）中，在RNA加工中具有关键作用的剪接体蛋白异常聚集并错误定位于Tau神经元缠结。我们测试的假设，Tau剪接体相互作用破坏前mRNA剪接在AD。在具有AD病理学的人死后脑中，Tau与剪接体组分共免疫沉淀。在果蝇中，泛神经元Tau表达触发了多个核心和U1特异性剪接体蛋白的减少，这些因子（包括SmB、U1- 70 K和U1 A）的遗传破坏增强了Tau介导的神经变性。我们进一步表明，SmB的功能丧失，编码核心剪接体蛋白，导致生存率下降，进行性运动障碍和神经元损失，独立于Tau毒性。最后，RNA测序揭示了SmB突变体和Tau转基因果蝇中mRNA剪接错误的相似特征，包括内含子保留和未注释的隐蔽剪接点。在人类大脑中，我们确认了与神经原纤维缠结负担相关的神秘拼接错误。我们的研究结果涉及剪接体破坏和由此产生的转录组扰动在AD中Tau介导的神经变性。
In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosomedisruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.