Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2018 Jun 5;23(10):2874-2880. doi: 10.1016/j.celrep.2018.05.004.
Aging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer's disease (AD). Leveraging RNA sequencing from 636 human brains, we discover differential expression for several retrotransposons in association with neurofibrillary tangle burden and highlight evidence for global TE transcriptional activation among the long interspersed nuclear element 1 and endogenous retrovirus clades. In addition, we detect Tau-associated, active chromatin signatures at multiple HERV-Fc1 genomic loci. To determine whether Tau is sufficient to induce TE activation, we profile retrotransposons in Drosophila expressing human wild-type or mutant Tau throughout the brain. We discover heterogeneous response profiles, including both age- and genotype-dependent activation of TE expression by Tau. Our results implicate TE activation and associated genomic instability in Tau-mediated AD mechanisms.
衰老和神经退行性疾病的特征是神经元中的基因组不稳定，包括转座元件（TEs）的异常激活和动员。我们整合了人类死后脑组织和黑腹果蝇模型的研究，研究了与阿尔茨海默病（AD）中 Tau 病理学相关的 TE 激活。利用来自 636 个人脑的 RNA 测序，我们发现了几种逆转录转座子与神经纤维缠结负担相关的差异表达，并强调了长散布核元件 1 和内源性逆转录病毒族之间的全局 TE 转录激活的证据。此外，我们在多个 HERV-Fc1 基因组位点检测到与 Tau 相关的活性染色质特征。为了确定 Tau 是否足以诱导 TE 激活，我们在整个大脑中表达人类野生型或突变型 Tau 的果蝇中对逆转录转座子进行了分析。我们发现了异质的反应谱，包括 Tau 对 TE 表达的年龄和基因型依赖性激活。我们的结果表明，TE 激活和相关的基因组不稳定性参与了 Tau 介导的 AD 机制。
