TY - JOUR
T1 - C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity
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.
N1 - Publisher Copyright:
© The Author 2017.
PY - 2017/12
Y1 - 2017/12
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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U2 - 10.1093/hmg/ddx350
DO - 10.1093/hmg/ddx350
M3 - Article
C2 - 28973350
AN - SCOPUS:85040192893
SN - 0964-6906
VL - 26
SP - 4765
EP - 4777
JO - Human molecular genetics
JF - Human molecular genetics
IS - 24
ER -