Maor-Nof, M., Shipony, Z., Lopez-Gonzalez, R., Nakayama, L., Zhang, Y.J., Couthouis, J., Blum, J.A., Castruita, P.A., Linares, G.R., Ruan, K., Ramaswami, G., Simon, D.J., Nof, A., Santana, M., Han, K., Sinnott-Armstrong, N., Bassik, M.C., Geschwind, D.H., Tessier-Lavigne, M., Attardi, L.D., Lloyd, T.E., Ichida, J.K., Gao, F.B., Greenleaf, W.J., Yokoyama, J.S., Petrucelli, L., Gitler, A.D. (2021). p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).  Cell 184(3): 689--708.e20.

FBrf0250319

Research paper

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.

PMC7886018 (PMC) (EuropePMC)