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

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. AttardiThomas E. Lloyd, Justin K. Ichida, Fen Biao Gao, William J. Greenleaf, Jennifer S. Yokoyama, Leonard Petrucelli, Aaron D. Gitler

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)689-708.e20
Issue number3
StatePublished - Feb 4 2021


  • ATAC-seq
  • C9orf72
  • TDP-43
  • amyotrophic lateral sclerosis
  • axonal degeneration
  • neurodegeneration
  • p53
  • puma

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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