RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention

Christopher J. Donnelly, Pingwu Zhang, Jacqueline T. Pham, Aaron R. Heusler, Nipun A. Mistry, Svetlana Vidensky, Elizabeth L. Daley, Erin M. Poth, Benjamin Hoover, Daniel M. Fines, Nicholas J Maragakis, Pentti J. Tienari, Leonard Petrucelli, Bryan J. Traynor, Jiou Wang, Frank Rigo, C. Frank Bennett, Seth Blackshaw, Rita Sattler, Jeffrey D Rothstein

Research output: Contribution to journalArticle


A hexanucleotide GGGGCC repeat expansion in the noncoding region of the C9ORF72 gene is the most common genetic abnormality in familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The function of the C9ORF72 protein is unknown, as is the mechanism by which the repeat expansion could cause disease. Induced pluripotent stem cell (iPSC)-differentiated neurons from C9ORF72 ALS patients revealed disease-specific (1) intranuclear GGGGCCexp RNA foci, (2) dysregulated gene expression, (3) sequestration of GGGGCCexp RNA binding protein ADARB2, and (4) susceptibility to excitotoxicity. These pathological and pathogenic characteristics were confirmed in ALS brain and were mitigated with antisense oligonucleotide (ASO) therapeutics to the C9ORF72 transcript or repeat expansion despite the presence of repeat-associated non-ATG translation (RAN) products. These data indicate a toxic RNA gain-of-function mechanism as a cause of C9ORF72 ALS and provide candidate antisense therapeutics and candidate human pharmacodynamic markers for therapy.

Original languageEnglish (US)
Pages (from-to)415-428
Number of pages14
Issue number2
StatePublished - Oct 16 2013


ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Donnelly, C. J., Zhang, P., Pham, J. T., Heusler, A. R., Mistry, N. A., Vidensky, S., Daley, E. L., Poth, E. M., Hoover, B., Fines, D. M., Maragakis, N. J., Tienari, P. J., Petrucelli, L., Traynor, B. J., Wang, J., Rigo, F., Bennett, C. F., Blackshaw, S., Sattler, R., & Rothstein, J. D. (2013). RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention. Neuron, 80(2), 415-428. https://doi.org/10.1016/j.neuron.2013.10.015