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 - Funding Information:
We thank Dr. Andrew Olson (Stanford Neuroscience Microscopy Service, supported by National Institutes of Health [NIH] grant NS069375 ). M.M.-N. is supported by an EMBO long-term fellowship ( ALTF 301-2017 ), the SSSI-Muscular Dystrophy Association (M.M.-N.), and Stanford School of Medicine Dean’s postdoctoral fellowships (M.M.-N.). This work was supported by NIH grants R35NS097263(10) (A.D.G.), R01NS094239 (T.E.L.), R01NS101986 (F.-B.G.), R37NS057553 (F.-B.G.), R35NS097273(17) (L.P.), P01NS084974 (L.P.), P01NS099114 (L.P.), R01NS089786 (M.T.L.), 1F32MH114620 (G.R.), K01AG049152 (J.S.Y.), R35CA197591 (L.D.A.), R01MH109912 (D.H.G.), R01NS097850 (J.K.I.), R01NS097850-01S1 (R.L.-G.), P50HG007735 (W.J.G.), R01HG008140 (W.J.G.), U19AI057266 (W.J.G.), UM1HG009442 (W.J.G.), and 1UM1HG009436 (W.J.G.); the Robert Packard Center for ALS Research at Johns Hopkins (A.D.G.); Target ALS (A.D.G., F.-B.G., J.C., L.P., and T.E.L.); the Blavatnik Family Foundation (J.A.B.); the Alzheimer's Association ( 2018-AARFD-592264 to G.R.L.); the Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute (A.D.G.); the U.S. Department of Defense (grant W81XWH-15-1- 0187 to J.K.I.); the Merkin Family Foundation (J.K.I.); the New York Stem Cell Foundation (J.K.I.); the John Douglas French Alzheimer’s Foundation ; and the Tau Consortium (J.K.I.). J.K.I. is a New York Stem Cell Foundation Robertson Investigator and a Richard N. Merkin Scholar. W.J.G. is a Chan Zuckerberg Biohub investigator. Some of the computing for this project was performed on the Sherlock cluster. We would like to thank Stanford University and the Stanford Research Computing Center for providing computational resources and support that contributed to these research results. This work used the Genome Sequencing Service Center by Stanford Center for Genomics and Personalized Medicine Sequencing Center, supported by NIH grant S10OD020141 . Some of the figures were created with BioRender.com.
Funding Information:
We thank Dr. Andrew Olson (Stanford Neuroscience Microscopy Service, supported by National Institutes of Health [NIH] grant NS069375). M.M.-N. is supported by an EMBO long-term fellowship (ALTF 301-2017), the SSSI-Muscular Dystrophy Association (M.M.-N.), and Stanford School of Medicine Dean's postdoctoral fellowships (M.M.-N.). This work was supported by NIH grants R35NS097263(10) (A.D.G.), R01NS094239 (T.E.L.), R01NS101986 (F.-B.G.), R37NS057553 (F.-B.G.), R35NS097273(17) (L.P.), P01NS084974 (L.P.), P01NS099114 (L.P.), R01NS089786 (M.T.L.), 1F32MH114620 (G.R.), K01AG049152 (J.S.Y.), R35CA197591 (L.D.A.), R01MH109912 (D.H.G.), R01NS097850 (J.K.I.), R01NS097850-01S1 (R.L.-G.), P50HG007735 (W.J.G.), R01HG008140 (W.J.G.), U19AI057266 (W.J.G.), UM1HG009442 (W.J.G.), and 1UM1HG009436 (W.J.G.); the Robert Packard Center for ALS Research at Johns Hopkins (A.D.G.); Target ALS (A.D.G. F.-B.G. J.C. L.P. and T.E.L.); the Blavatnik Family Foundation (J.A.B.); the Alzheimer's Association (2018-AARFD-592264 to G.R.L.); the Brain Rejuvenation Project of the Wu Tsai Neurosciences Institute (A.D.G.); the U.S. Department of Defense (grant W81XWH-15-1- 0187 to J.K.I.); the Merkin Family Foundation (J.K.I.); the New York Stem Cell Foundation (J.K.I.); the John Douglas French Alzheimer's Foundation; and the Tau Consortium (J.K.I.). J.K.I. is a New York Stem Cell Foundation Robertson Investigator and a Richard N. Merkin Scholar. W.J.G. is a Chan Zuckerberg Biohub investigator. Some of the computing for this project was performed on the Sherlock cluster. We would like to thank Stanford University and the Stanford Research Computing Center for providing computational resources and support that contributed to these research results. This work used the Genome Sequencing Service Center by Stanford Center for Genomics and Personalized Medicine Sequencing Center, supported by NIH grant S10OD020141. Some of the figures were created with BioRender.com. Conceptualization, M.M.-N. and A.D.G.; Methodology, M.M.-N. Z.S. and A.N.; Investigation, M.M.-N. R.L.-G. L.N. Y.-J.Z. J.C. J.A.B. P.A.C. G.R.L. K.R. G.R. D.J.S. A.N. M.S. K.H. and N.S.-A.; Writing – Original Draft, M.M.-N. and A.D.G.; Writing – Review & Editing, M.M.-N. M.C.B. D.H.G. M.T.-L. L.D.A. T.E.L. J.K.I. F.-B.G. W.J.G. J.S.Y. L.P. and A.D.G.; Funding Acquisition, A.D.G.; Supervision, M.C.B. D.H.G. M.T.-L. L.D.A. T.E.L. J.K.I. F.-B.G. W.J.G. J.S.Y. L.P. and A.D.G. A.D.G. has served as a consultant for Aquinnah Pharmaceuticals, Prevail Therapeutics, and Third Rock Ventures and is a scientific founder of Maze Therapeutics. W.J.G. has affiliations with 10x Genomics (consultant), Guardant Health (consultant), and Protillion Biosciences (co-founder and consultant). J.K.I. is a co-founder of Acurastem. D.H.G has served as a consultant for Acurastem, Axial Biosciences, and Roche
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 -