C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity

Youn Bok Lee, Pranetha Baskaran, Jorge Gomez-Deza, Han Jou Chen, Agnes L. Nishimura, Bradley N. Smith, Claire Troakes, Yoshitsugu Adachi, Alan Stepto, Leonard Petrucelli, Jean Marc Gallo, Frank Hirth, Boris Rogelj, Sarah Guthrie, Christopher E. Shaw

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culturemodel activates programmed cell death and TDP-43 cleavage in a dose-dependentmanner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being themost toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a keymediator of cytotoxicity and that cross-talk between DPR proteins likelymodifies their pathogenic status in C9ALS/FTD.

Original languageEnglish (US)
Pages (from-to)4765-4777
Number of pages13
JournalHuman Molecular Genetics
Volume26
Issue number24
DOIs
StatePublished - Dec 1 2017

Fingerprint

Amyotrophic Lateral Sclerosis
Dipeptides
Spinal Cord
Cell Death
RNA
Intranuclear Inclusion Bodies
Proteins
Poisons
Inclusion Bodies
Codon
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Lee, Y. B., Baskaran, P., Gomez-Deza, J., Chen, H. J., Nishimura, A. L., Smith, B. N., ... Shaw, C. E. (2017). C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity. Human Molecular Genetics, 26(24), 4765-4777. https://doi.org/10.1093/hmg/ddx350

C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity. / Lee, Youn Bok; Baskaran, Pranetha; Gomez-Deza, Jorge; Chen, Han Jou; Nishimura, Agnes L.; Smith, Bradley N.; Troakes, Claire; Adachi, Yoshitsugu; Stepto, Alan; Petrucelli, Leonard; Gallo, Jean Marc; Hirth, Frank; Rogelj, Boris; Guthrie, Sarah; Shaw, Christopher E.

In: Human Molecular Genetics, Vol. 26, No. 24, 01.12.2017, p. 4765-4777.

Research output: Contribution to journalArticle

Lee, YB, Baskaran, P, Gomez-Deza, J, Chen, HJ, Nishimura, AL, Smith, BN, Troakes, C, Adachi, Y, Stepto, A, Petrucelli, L, Gallo, JM, Hirth, F, Rogelj, B, Guthrie, S & Shaw, CE 2017, 'C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity', Human Molecular Genetics, vol. 26, no. 24, pp. 4765-4777. https://doi.org/10.1093/hmg/ddx350
Lee, Youn Bok ; Baskaran, Pranetha ; Gomez-Deza, Jorge ; Chen, Han Jou ; Nishimura, Agnes L. ; Smith, Bradley N. ; Troakes, Claire ; Adachi, Yoshitsugu ; Stepto, Alan ; Petrucelli, Leonard ; Gallo, Jean Marc ; Hirth, Frank ; Rogelj, Boris ; Guthrie, Sarah ; Shaw, Christopher E. / C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 24. pp. 4765-4777.
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abstract = "An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culturemodel activates programmed cell death and TDP-43 cleavage in a dose-dependentmanner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being themost toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a keymediator of cytotoxicity and that cross-talk between DPR proteins likelymodifies their pathogenic status in C9ALS/FTD.",
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AU - Lee, Youn Bok

AU - Baskaran, Pranetha

AU - Gomez-Deza, Jorge

AU - Chen, Han Jou

AU - Nishimura, Agnes L.

AU - Smith, Bradley N.

AU - Troakes, Claire

AU - Adachi, Yoshitsugu

AU - Stepto, Alan

AU - Petrucelli, Leonard

AU - Gallo, Jean Marc

AU - Hirth, Frank

AU - Rogelj, Boris

AU - Guthrie, Sarah

AU - Shaw, Christopher E.

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N2 - An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culturemodel activates programmed cell death and TDP-43 cleavage in a dose-dependentmanner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being themost toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a keymediator of cytotoxicity and that cross-talk between DPR proteins likelymodifies their pathogenic status in C9ALS/FTD.

AB - An intronic GGGGCC (G4C2) hexanucleotide repeat expansion inC9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 RNA can result in five different dipeptide repeat proteins (DPR: poly GA, poly GP, poly GR, poly PA, and poly PR), which aggregate into neuronal cytoplasmic and nuclear inclusions in affected patients, however their contribution to disease pathogenesis remains controversial. We show that among the DPR proteins, expression of poly GA in a cell culturemodel activates programmed cell death and TDP-43 cleavage in a dose-dependentmanner. Dual expression of poly GA together with other DPRs revealed that poly GP and poly PA are sequestered by poly GA, whereas poly GR and poly PR are rarely co-localised with poly GA. Dual expression of poly GA and poly PA ameliorated poly GA toxicity by inhibiting poly GA aggregation both in vitro and in vivo in the chick embryonic spinal cord. Expression of alternative codon-derived DPRs in chick embryonic spinal cord confirmed in vitro data, revealing that each of the dipeptides caused toxicity, with poly GA being themost toxic. Further, in vivo expression of G4C2 repeats of varying length caused apoptotic cell death, but failed to generate DPRs. Together, these data demonstrate that C9-related toxicity can be mediated by either RNA or DPRs. Moreover, our findings provide evidence that poly GA is a keymediator of cytotoxicity and that cross-talk between DPR proteins likelymodifies their pathogenic status in C9ALS/FTD.

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