Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts

Nicholas J. Kramer, Yari Carlomagno, Yong Jie Zhang, Sandra Almeida, Casey N. Cook, Tania F. Gendron, Mercedes Prudencio, Marka Van Blitterswijk, Veronique Belzil, Julien Couthouis, Joseph West Paul, Lindsey D. Goodman, Lillian Daughrity, Jeannie Chew, Aliesha Garrett, Luc Pregent, Karen Jansen-West, Lilia J. Tabassian, Rosa Rademakers, Kevin BoylanNeill R. Graff-Radford, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Bradley F. Boeve, Ning Deng, Yanan Feng, Tzu Hao Cheng, Dennis W. Dickson, Stanley N. Cohen, Nancy M. Bonini, Christopher D. Link, Fen Biao Gao, Leonard Petrucelli, Aaron D. Gitler

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics are being developed to target RNAs containing the expanded repeat sequence (GGGGCC); however, this approach is complicated by the presence of antisense strand transcription of expanded GGCCCC repeats.We found that targeting the transcription elongation factor Spt4 selectively decreased production of both sense and antisense expanded transcripts, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1, the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci, as well as DPR proteins, in patient cells. Therapeutic targeting of a single factor to eliminate c9FTD/ALS pathological features offers advantages over approaches that require targeting sense and antisense repeats separately.

Original languageEnglish (US)
Pages (from-to)708-712
Number of pages5
Issue number6300
StatePublished - Aug 12 2016

ASJC Scopus subject areas

  • General


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