Chromatin accessibility profiling in neurons reveals p53 as a central regulator driving neurodegeneration caused by ALS/FTD-associated C9orf72 polyPR

Topic:

Scientific Other

Poster Number: 232

Author(s):

Maya Maor Nof, PhD, Zohar Shipony, PhD, Lisa Nakayama, Zhang Yong-Jie, Julien Couthouis, PhD, Jacob Blum, Patricia Castruita, PhD, Rodrigo Lopez-Gonzalez, PhD, Gabriel Linares, PhD, Kai Ruan, PhD, Gokul Ramaswami, PhD, David Simon, PhD, Aviv Nof, Kyuho Han, PhD, Michael Bassik, PhD, Daniel Geschwind, MD, PhD, Marc Tessier-Lavigne, PhD, Laura Attardi, PhD, Thomas Lloyd, MD, PhD, Justin Ichida, PhD, Fen-Biao Gao, PhD, William Greenleaf, PhD, Jennifer Yokoyama, PhD, Leonard Petrucelli, PhD, Aaron Gitler, PhD

Institutions:

1. stanford university, 2. stanford university, 3. stanford university, 4. Mayo Clinic, 5. stanford university, 6. stanford university, 7. UCSF, 8. umass, 9. USC, 10. Johns Hopkins University, 11. UCLA, 12. Cornell, 14. Stanford university, 15. Stanford university, 16. UCLA, 17. Stanford university, 18. Stanford university, 19. Johns Hopkins University, 20. University of Southern California, 21. UMASS, 22. Stanford university, 23. UCSF, 24. mayo clinic , 24. Stanford university

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative diseases that share genetic and neuropathological features. The most common genetic cause of both ALS and FTD is a GGGGCC repeat expansion in the C9orf72 gene. How C9orf72 mutations contribute to neurodegeneration is not fully understood. To study the cellular mechanisms driving neurodegeneration, we developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons in response to pathogenic protein accumulation. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 hexanucleotide repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from cell death and axonal degeneration and markedly increased survival in a C9orf72 mouse model. Furthermore, p53 reduction was sufficient to rescue C9orf72 ALS/FTD patient iPSC-derived motor neurons from DNA damage and mitigate neurodegeneration in a C9orf72 fly model. Mechanistically, we show that p53 is stabilized, binds to DNA and activates a downstream transcriptional program, including Puma, which drives neurodegeneration. Finally, integrating human genetics data with protein interaction networks reveals p53 as a central hub gene within a functional protein interaction network specific to ALS but not several other neurodegenerative diseases. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription factor binding events controlling gene expression programs and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.