TY - JOUR
T1 - Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs
AU - Jiang, Jie
AU - Zhu, Qiang
AU - Gendron, Tania F.
AU - Saberi, Shahram
AU - McAlonis-Downes, Melissa
AU - Seelman, Amanda
AU - Stauffer, Jennifer E.
AU - Jafar-nejad, Paymaan
AU - Drenner, Kevin
AU - Schulte, Derek
AU - Chun, Seung
AU - Sun, Shuying
AU - Ling, Shuo Chien
AU - Myers, Brian
AU - Engelhardt, Jeffery
AU - Katz, Melanie
AU - Baughn, Michael
AU - Platoshyn, Oleksandr
AU - Marsala, Martin
AU - Watt, Andy
AU - Heyser, Charles J.
AU - Ard, M. Colin
AU - De Muynck, Louis
AU - Daughrity, Lillian M.
AU - Swing, Deborah A.
AU - Tessarollo, Lino
AU - Jung, Chris J.
AU - Delpoux, Arnaud
AU - Utzschneider, Daniel T.
AU - Hedrick, Stephen M.
AU - de Jong, Pieter J.
AU - Edbauer, Dieter
AU - Van Damme, Philip
AU - Petrucelli, Leonard
AU - Shaw, Christopher E.
AU - Bennett, C. Frank
AU - Da Cruz, Sandrine
AU - Ravits, John
AU - Rigo, Frank
AU - Cleveland, Don W.
AU - Lagier-Tourenne, Clotilde
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/4
Y1 - 2016/5/4
N2 - Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy. Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of ALS and FTD. Jiang et al. establish gain of toxicity from repeat-containing RNA, and not loss of C9ORF72 function, as a central disease mechanism and establish the feasibility of ASO-mediated therapy.
AB - Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, increased anxiety, and impaired cognitive function. Single-dose injection of antisense oligonucleotides (ASOs) that target repeat-containing RNAs but preserve levels of mRNAs encoding C9ORF72 produced sustained reductions in RNA foci and dipeptide-repeat proteins, and ameliorated behavioral deficits. These efforts identify gain of toxicity as a central disease mechanism caused by repeat-expanded C9ORF72 and establish the feasibility of ASO-mediated therapy. Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of ALS and FTD. Jiang et al. establish gain of toxicity from repeat-containing RNA, and not loss of C9ORF72 function, as a central disease mechanism and establish the feasibility of ASO-mediated therapy.
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U2 - 10.1016/j.neuron.2016.04.006
DO - 10.1016/j.neuron.2016.04.006
M3 - Article
C2 - 27112497
AN - SCOPUS:84963959793
SN - 0896-6273
VL - 90
SP - 535
EP - 550
JO - Neuron
JF - Neuron
IS - 3
ER -