Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

Junli Gao; Quinlan T. Mewborne; Amandeep Girdhar; Udit Sheth; Alyssa N. Coyne; Ritika Punathil; Bong Gu Kang; Morgan Dasovich; Austin Veire; Mariely DeJesus Hernandez; Shuaichen Liu; Zheng Shi; Ruxandra Dafinca; Elise Fouquerel; Kevin Talbot; Tae In Kam; Yong Jie Zhang; Dennis Dickson; Leonard Petrucelli; Marka van Blitterswijk; Lin Guo; Ted M. Dawson; Valina L. Dawson; Anthony K.L. Leung; Thomas E. Lloyd; Tania F. Gendron; Jeffrey D. Rothstein; Ke Zhang

doi:10.1126/scitranslmed.abq3215

Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

Junli Gao, Quinlan T. Mewborne, Amandeep Girdhar, Udit Sheth, Alyssa N. Coyne, Ritika Punathil, Bong Gu Kang, Morgan Dasovich, Austin Veire, Mariely DeJesus Hernandez, Shuaichen Liu, Zheng Shi, Ruxandra Dafinca, Elise Fouquerel, Kevin Talbot, Tae In Kam, Yong Jie Zhang, Dennis Dickson, Leonard Petrucelli, Marka van BlitterswijkLin Guo, Ted M. Dawson, Valina L. Dawson, Anthony K.L. Leung, Thomas E. Lloyd, Tania F. Gendron, Jeffrey D. Rothstein, Ke Zhang

Research output: Contribution to journal › Article › peer-review

Abstract

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72, play a critical role in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR-induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.

Original language	English (US)
Article number	abq3215
Journal	Science translational medicine
Volume	14
Issue number	662
DOIs	https://doi.org/10.1126/scitranslmed.abq3215
State	Published - Sep 14 2022

ASJC Scopus subject areas

General Medicine

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Gao, J., Mewborne, Q. T., Girdhar, A., Sheth, U., Coyne, A. N., Punathil, R., Kang, B. G., Dasovich, M., Veire, A., DeJesus Hernandez, M., Liu, S., Shi, Z., Dafinca, R., Fouquerel, E., Talbot, K., Kam, T. I., Zhang, Y. J., Dickson, D., Petrucelli, L., ... Zhang, K. (2022). Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins. Science translational medicine, 14(662), Article abq3215. https://doi.org/10.1126/scitranslmed.abq3215

Gao, J, Mewborne, QT, Girdhar, A, Sheth, U, Coyne, AN, Punathil, R, Kang, BG, Dasovich, M, Veire, A, DeJesus Hernandez, M, Liu, S, Shi, Z, Dafinca, R, Fouquerel, E, Talbot, K, Kam, TI, Zhang, YJ, Dickson, D, Petrucelli, L, van Blitterswijk, M, Guo, L, Dawson, TM , Dawson, VL , Leung, AKL, Lloyd, TE, Gendron, TF, Rothstein, JD & Zhang, K 2022, 'Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins', Science translational medicine, vol. 14, no. 662, abq3215. https://doi.org/10.1126/scitranslmed.abq3215

@article{73aa9de2f3844b71b5a414249079e55e,

title = "Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins",

abstract = "Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72, play a critical role in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR-induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.",

author = "Junli Gao and Mewborne, {Quinlan T.} and Amandeep Girdhar and Udit Sheth and Coyne, {Alyssa N.} and Ritika Punathil and Kang, {Bong Gu} and Morgan Dasovich and Austin Veire and {DeJesus Hernandez}, Mariely and Shuaichen Liu and Zheng Shi and Ruxandra Dafinca and Elise Fouquerel and Kevin Talbot and Kam, {Tae In} and Zhang, {Yong Jie} and Dennis Dickson and Leonard Petrucelli and {van Blitterswijk}, Marka and Lin Guo and Dawson, {Ted M.} and Dawson, {Valina L.} and Leung, {Anthony K.L.} and Lloyd, {Thomas E.} and Gendron, {Tania F.} and Rothstein, {Jeffrey D.} and Ke Zhang",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

month = sep,

day = "14",

doi = "10.1126/scitranslmed.abq3215",

language = "English (US)",

volume = "14",

journal = "Science translational medicine",

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publisher = "American Association for the Advancement of Science",

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T1 - Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

AU - Gao, Junli

AU - Mewborne, Quinlan T.

AU - Girdhar, Amandeep

AU - Sheth, Udit

AU - Coyne, Alyssa N.

AU - Punathil, Ritika

AU - Kang, Bong Gu

AU - Dasovich, Morgan

AU - Veire, Austin

AU - DeJesus Hernandez, Mariely

AU - Liu, Shuaichen

AU - Shi, Zheng

AU - Dafinca, Ruxandra

AU - Fouquerel, Elise

AU - Talbot, Kevin

AU - Kam, Tae In

AU - Zhang, Yong Jie

AU - Dickson, Dennis

AU - Petrucelli, Leonard

AU - van Blitterswijk, Marka

AU - Guo, Lin

AU - Dawson, Ted M.

AU - Dawson, Valina L.

AU - Leung, Anthony K.L.

AU - Lloyd, Thomas E.

AU - Gendron, Tania F.

AU - Rothstein, Jeffrey D.

AU - Zhang, Ke

PY - 2022/9/14

Y1 - 2022/9/14

N2 - Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72, play a critical role in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR-induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.

AB - Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72, play a critical role in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR-induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.

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U2 - 10.1126/scitranslmed.abq3215

DO - 10.1126/scitranslmed.abq3215

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C2 - 36103513

AN - SCOPUS:85138444989

SN - 1946-6234

VL - 14

JO - Science translational medicine

JF - Science translational medicine

IS - 662

M1 - abq3215

ER -

Poly(ADP-ribose) promotes toxicity of C9ORF72 arginine-rich dipeptide repeat proteins

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