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

Cell. 2021 Feb 4;184(3):689-708.e20. doi: 10.1016/j.cell.2020.12.025. Epub 2021 Jan 21.

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.

Keywords: ATAC-seq; C9orf72; TDP-43; amyotrophic lateral sclerosis; axonal degeneration; neurodegeneration; p53; puma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Axons / metabolism
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism*
  • Cell Death
  • Cells, Cultured
  • Cerebral Cortex / pathology
  • Chromatin / metabolism
  • DNA Damage
  • DNA Repeat Expansion / genetics*
  • Disease Models, Animal
  • Drosophila
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Protein Stability
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • C9orf72 Protein
  • Chromatin
  • PUMA protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins