Journal
SCIENCE
Volume 353, Issue 6300, Pages 708-712Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaf7791
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Funding
- NIH [R01NS065317, R01NS09386501, R01NS073660, R01AG026251, R21NS079807, R21NS094489, R01NS063964, R01NS077402, R21NS084528, P01NS084974, R01NS088689, R01ES20395, R01NS085812, R01NS079725]
- Mayo Clinic Foundation
- Alzheimer's Association [NIRP-14-304425]
- Amyotrophic Lateral Sclerosis Association
- National Science Foundation Graduate Research Fellowship
- Robert Packard Center for ALS Research at Johns Hopkins
- Target ALS
- Association for Frontotemporal Degeneration
- Stanford University
- Glenn Foundation
- Hoffmann-La Roche, Inc.
- Merck, Inc.
- Genentech, Inc.
- Biogen, Inc.
- Eli Lilly Co.
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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.
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