| Literature DB >> 27516603 |
Nicholas J Kramer1, Yari Carlomagno2, Yong-Jie Zhang2, Sandra Almeida3, Casey N Cook2, Tania F Gendron2, Mercedes Prudencio2, Marka Van Blitterswijk2, Veronique Belzil2, Julien Couthouis4, Joseph West Paul4, Lindsey D Goodman5, Lillian Daughrity2, Jeannie Chew2, Aliesha Garrett2, Luc Pregent2, Karen Jansen-West2, Lilia J Tabassian2, Rosa Rademakers2, Kevin Boylan6, Neill R Graff-Radford6, Keith A Josephs7, Joseph E Parisi7, David S Knopman7, Ronald C Petersen7, Bradley F Boeve7, Ning Deng4, Yanan Feng4, Tzu-Hao Cheng8, Dennis W Dickson2, Stanley N Cohen4, Nancy M Bonini5, Christopher D Link9, Fen-Biao Gao3, Leonard Petrucelli10, Aaron D Gitler11.
Abstract
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.Entities:
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Year: 2016 PMID： 27516603 PMCID： PMC5823025 DOI： 10.1126/science.aaf7791
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728