Journal
CELL
Volume 184, Issue 3, Pages 689-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.12.025
Keywords
-
Categories
Funding
- National Institutes of Health [NIH] [NS069375]
- EMBO long-term fellowship [ALTF 301-2017]
- SSSI-Muscular Dystrophy Association
- Stanford School of Medicine Dean's postdoctoral fellowships
- NIH [S10OD020141, R35NS097263(10), R01NS094239, R01NS101986, R37NS057553, R35NS097273(17), P01NS084974]
- Target ALS
- Blavatnik Family Foundation
- Alzheimer's Association [2018-AARFD-592264]
- Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute
- U.S. Department of Defense [W81XWH-15-1-0187]
- Merkin Family Foundation
- New York Stem Cell Foundation
- John Douglas French Alzheimer's Foundation
- Tau Consortium
- Stanford University
- Stanford Research Computing Center
- The NIH [P01NS099114, R01NS089786, 1F32MH114620, K01AG049152, R35CA197591, R01MH109912, R01NS097850, R01NS097850-01S1, P50HG007735, R01HG008140, U19AI057266, UM1HG009442, 1UM1HG009436]
Ask authors/readers for more resources
The repeat expansion in the C9orf72 gene leads to activation of a specific transcriptional program, causing neurodegeneration. Removing p53 in experiments successfully rescued neuronal degeneration and extended survival.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available