Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Cell. 2021 Feb 4;184(3):689-708.e20. doi: 10.1016/j.cell.2020.12.025. Epub 2021 Jan 21.
The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.
最常见的肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的遗传原因是 C9orf72 基因中的 GGGGCC 重复扩展。我们开发了一个平台来研究神经元退化过程中的染色质可及性景观和转录程序。我们提供的证据表明，表达二肽重复蛋白多脯氨酸-精氨酸的神经元，从 C9orf72 重复扩展翻译而来，激活了一个高度特异性的转录程序，以转录因子 p53 为例。在小鼠中敲除 p53 可完全防止神经元退化，并显著增加 C9orf72 小鼠模型中的存活。p53 减少还可挽救多甘氨酸-精氨酸引起的轴突变性，增加 C9orf72 ALS/FTD-患者诱导多能干细胞（iPSC）衍生运动神经元的存活，并减轻 C9orf72 果蝇模型中的神经退行性变。我们表明 p53 激活了一个下游转录程序，包括 Puma，其驱动神经退行性变。这些数据表明，通过转录因子结合事件动态调节神经退行性变机制，并为应用染色质可及性和转录程序谱进行神经退行性变提供了框架。
