Prudencio Mercedes, Gonzales Patrick K, Cook Casey N, Gendron Tania F, Daughrity Lillian M, Song Yuping, Ebbert Mark T W, van Blitterswijk Marka, Zhang Yong-Jie, Jansen-West Karen, Baker Matthew C, DeTure Michael, Rademakers Rosa, Boylan Kevin B, Dickson Dennis W, Petrucelli Leonard, Link Christopher D
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA.
Hum Mol Genet. 2017 Sep 1;26(17):3421-3431. doi: 10.1093/hmg/ddx233.
Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD.
在肌萎缩侧索硬化症（ALS）患者的大脑中检测到显著的转录组改变，包括携带C9orf72重复扩增的患者以及C9orf72阴性的散发性病例。最近，重复元件转录本的表达与毒性相关，虽然在几种神经退行性疾病中观察到重复元件表达增加，但对于它们在ALS中的作用知之甚少。为了评估ALS中是否存在重复元件序列的异常表达，我们分析了来自C9orf72阳性和散发性ALS病例以及健康对照的RNA测序数据。C9orf72 ALS患者额叶皮质中多个类别和亚类的重复元件（长散在核元件、内源性逆转录病毒、DNA转座子、简单重复序列等）的转录本显著增加。使用大量代表C9orf72阳性和阴性ALS、ALS/额颞叶痴呆（FTLD）以及FTLD病例的患者样本，来验证几种重复元件转录本的水平。这些分析证实，与C9orf72阴性或对照病例相比，C9orf72阳性病例中的重复元件表达显著增加。虽然先前的研究表明TDP-43与重复元件生物学之间存在重要联系，但我们的数据表明，仅TDP-43病理学不足以解释ALS/FTLD中观察到的重复元件变化。相反，我们发现重复元件表达与死后大脑中的RNA聚合酶II活性呈正相关，并且RNA聚合酶II活性的药理学调节在体外改变了重复元件表达。我们得出结论，ALS/FTLD中RNA聚合酶II活性增加可能导致重复元件转录本表达增加，这是ALS/FTLD的一种新的病理特征。
