| First Author | Maor-Nof M | Year | 2021 |
| Journal | Cell | Volume | 184 |
| Issue | 3 | Pages | 689-708.e20 |
| PubMed ID | 33482083 | Mgi Jnum | J:302558 |
| Mgi Id | MGI:6508467 | Doi | 10.1016/j.cell.2020.12.025 |
| Citation | Maor-Nof M, et al. (2021) p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell 184(3):689-708.e20 |
| abstractText | 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. |
