TY - JOUR
T1 - p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)
AU - Maor-Nof, Maya
AU - Shipony, Zohar
AU - Lopez-Gonzalez, Rodrigo
AU - Nakayama, Lisa
AU - Zhang, Yong Jie
AU - Couthouis, Julien
AU - Blum, Jacob A.
AU - Castruita, Patricia A.
AU - Linares, Gabriel R.
AU - Ruan, Kai
AU - Ramaswami, Gokul
AU - Simon, David J.
AU - Nof, Aviv
AU - Santana, Manuel
AU - Han, Kyuho
AU - Sinnott-Armstrong, Nasa
AU - Bassik, Michael C.
AU - Geschwind, Daniel H.
AU - Tessier-Lavigne, Marc
AU - Attardi, Laura D.
AU - Lloyd, Thomas E.
AU - Ichida, Justin K.
AU - Gao, Fen Biao
AU - Greenleaf, William J.
AU - Yokoyama, Jennifer S.
AU - Petrucelli, Leonard
AU - Gitler, Aaron D.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/2/4
Y1 - 2021/2/4
N2 - 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.
AB - 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.
KW - ATAC-seq
KW - C9orf72
KW - TDP-43
KW - amyotrophic lateral sclerosis
KW - axonal degeneration
KW - neurodegeneration
KW - p53
KW - puma
UR - http://www.scopus.com/inward/record.url?scp=85100427326&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100427326&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2020.12.025
DO - 10.1016/j.cell.2020.12.025
M3 - Article
C2 - 33482083
AN - SCOPUS:85100427326
SN - 0092-8674
VL - 184
SP - 689-708.e20
JO - Cell
JF - Cell
IS - 3
ER -