p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)
In: Cell, Jg. 184 (2021-02-01), Heft 3
Online
academicJournal
- 689 - 708.e20
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.
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p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR)
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Autor/in / Beteiligte Person: | Maor-Nof, Maya ; Shipony, Zohar ; Lopez-Gonzalez, Rodrigo ; Nakayama, Lisa ; Zhang, Yong-Jie ; Couthouis, Julien ; Blum, Jacob A ; Castruita, Patricia A ; Linares, Gabriel R ; Ruan, Kai ; Ramaswami, Gokul ; Simon, David J ; Nof, Aviv ; Santana, Manuel ; Han, Kyuho ; Sinnott-Armstrong, Nasa ; Bassik, Michael C ; Geschwind, Daniel H ; Tessier-Lavigne, Marc ; Attardi, Laura D ; Lloyd, Thomas E ; Ichida, Justin K ; Gao, Fen-Biao ; Greenleaf, William J ; Yokoyama, Jennifer S ; Petrucelli, Leonard ; Gitler, Aaron D |
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Zeitschrift: | Cell, Jg. 184 (2021-02-01), Heft 3 |
Veröffentlichung: | eScholarship, University of California, 2021 |
Medientyp: | academicJournal |
Umfang: | 689 - 708.e20 |
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