학술논문
p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)
Document Type
article
Author
Maor-Nof, Maya; Shipony, Zohar; Lopez-Gonzalez, Rodrigo; Nakayama, Lisa; Zhang, Yong-Jie; Couthouis, Julien; Blum, Jacob A; Castruita, Patricia A; Linares, Gabriel R; Ruan, Kai; Ramaswami, Gokul; Simon, David J; Nof, Aviv; Santana, Manuel; Han, Kyuho; Sinnott-Armstrong, Nasa; Bassik, Michael C; Geschwind, Daniel H; Tessier-Lavigne, Marc; Attardi, Laura D; Lloyd, Thomas E; Ichida, Justin K; Gao, Fen-Biao; Greenleaf, William J; Yokoyama, Jennifer S; Petrucelli, Leonard; Gitler, Aaron D
Source
Cell. 184(3)
Subject
Language
Abstract
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.