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Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.


ABSTRACT: 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.

SUBMITTER: Jiang J 

PROVIDER: S-EPMC4860075 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs.

Jiang Jie J   Zhu Qiang Q   Gendron Tania F TF   Saberi Shahram S   McAlonis-Downes Melissa M   Seelman Amanda A   Stauffer Jennifer E JE   Jafar-Nejad Paymaan P   Drenner Kevin K   Schulte Derek D   Chun Seung S   Sun Shuying S   Ling Shuo-Chien SC   Myers Brian B   Engelhardt Jeffery J   Katz Melanie M   Baughn Michael M   Platoshyn Oleksandr O   Marsala Martin M   Watt Andy A   Heyser Charles J CJ   Ard M Colin MC   De Muynck Louis L   Daughrity Lillian M LM   Swing Deborah A DA   Tessarollo Lino L   Jung Chris J CJ   Delpoux Arnaud A   Utzschneider Daniel T DT   Hedrick Stephen M SM   de Jong Pieter J PJ   Edbauer Dieter D   Van Damme Philip P   Petrucelli Leonard L   Shaw Christopher E CE   Bennett C Frank CF   Da Cruz Sandrine S   Ravits John J   Rigo Frank F   Cleveland Don W DW   Lagier-Tourenne Clotilde C  

Neuron 20160421 3


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 a  ...[more]

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