Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2019 Oct 8;29(2):301-316.e10. doi: 10.1016/j.celrep.2019.08.104.
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 spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.
在阿尔茨海默病（AD）中，具有关键 RNA 加工作用的剪接体蛋白异常聚集并错误定位到 Tau 神经原纤维缠结中。我们检验了以下假说，即 Tau-剪接体相互作用会破坏 AD 中的前体 mRNA 剪接。在具有 AD 病理的人类尸检大脑中，Tau 与剪接体成分共免疫沉淀。在果蝇中，泛神经元 Tau 表达会引发多种核心和 U1 特异性剪接体蛋白减少，而这些因素的遗传破坏，包括 SmB、U1-70K 和 U1A，会增强 Tau 介导的神经退行性变。我们进一步表明，编码核心剪接体蛋白的 SmB 功能丧失会导致存活减少、进行性运动障碍和神经元丧失，而与 Tau 毒性无关。最后，RNA 测序揭示了 SmB 突变体和 Tau 转基因果蝇中存在相似的 mRNA 剪接错误谱，包括内含子保留和未注释的隐秘剪接接头。在人类大脑中，我们证实了与神经原纤维缠结负担相关的隐秘剪接错误。我们的结果表明，剪接体功能障碍以及由此产生的转录组扰动与 AD 中 Tau 介导的神经退行性变有关。
