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  • p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

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

Cell (2021-01-23)
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
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.

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