美国斯坦福大学Aaron D. Gitler等研究人员合作发现，p53是驱动由C9orf72 poly(PR)引发神经退行性的核心调节因子。相关论文于2021年1月21日在线发表于国际学术期刊《细胞》。

研究人员开发了一个平台，可以在退行性过程中揭示神经元内的染色质可及性和转录程序。证据表明，表达二肽重复蛋白聚脯氨酸-精氨酸（由C9orf72重复扩增翻译而来）的神经元激活了高度特异性的转录程序，例如转录因子p53。在C9orf72小鼠模型中，敲除小鼠中的p53可以完全挽救神经元退行性，并显著提高存活率。

p53的降低还挽救了聚甘氨酸-精氨酸引起的轴突变性，增加了C9orf72肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）患者诱导多能干细胞（iPSC）衍生的运动神经元存活，并减轻了C9orf72果蝇模型的神经退行性。研究人员揭示出p53激活的下游转录程序，包括驱动神经退行性的Puma。

这些数据证明了通过转录因子结合事件动态调节的神经退行性机制，并提供了将染色质可及性和转录程序应用于神经退行性的框架。

据悉，ALS和FTD最常见遗传原因是C9orf72基因中的GGGGCC重复扩增。

附：英文原文

Title: p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)

Author: Maya Maor-Nof, Zohar Shipony, Rodrigo Lopez-Gonzalez, Lisa Nakayama, Yong-Jie Zhang, Julien Couthouis, Jacob A. Blum, Patricia A. Castruita, Gabriel R. Linares, Kai Ruan, Gokul Ramaswami, David J. Simon, Aviv Nof, Manuel Santana, Kyuho Han, Nasa Sinnott-Armstrong, Michael C. Bassik, Daniel H. Geschwind, Marc Tessier-Lavigne, Laura D. Attardi, Thomas E. Lloyd, Justin K. Ichida, Fen-Biao Gao, William J. Greenleaf, Jennifer S. Yokoyama, Leonard Petrucelli, Aaron D. Gitler

Issue&Volume: 2021-01-21

Abstract: The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporaldementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscapeand transcriptional program within neurons during degeneration. We provide evidencethat neurons expressing the dipeptide repeat protein poly(proline-arginine), translatedfrom the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplifiedby a single transcription factor, p53. Ablating p53 in mice completely rescued neuronsfrom 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 mitigatedneurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, includingPuma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanismdynamically regulated through transcription-factor-binding events and provide a frameworkto apply chromatin accessibility and transcription program profiles to neurodegeneration.

DOI: 10.1016/j.cell.2020.12.025

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31747-5