Journal
NEURON
Volume 83, Issue 5, Pages 1043-1050Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2014.07.041
Keywords
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Categories
Funding
- National Institutes of Health (NIH)/National Institute on Aging [R01GM097455, R01AG026251]
- NIH/National Institute of Neurological Disorders and Stroke [R21NS074121, R21NS079807, R21NS084528, R01NS088689, R01NS063964, R01NS077402, R01NS050557]
- ARRA Award [RC2-NS070-342, P01NS084974]
- National Institute of Environmental Health Services [R01 ES20395]
- Department of Defense [ALSRP AL130125]
- Intramural Program of the NIH, the National Institute on Aging [Z01-AG000949- 02]
- National Institute of Neurological Disorders and Stroke [Z01 NS002976-16]
- Mayo Clinic Foundation
- Mayo Clinic Center for Regenerative Medicine
- Mayo Clinic Center for Individualized Medicine
- ALS Association
- Alzheimer's Association
- Robert Packard Center for ALS Research at Johns Hopkins
- Target ALS
- Canadian Institutes of Health Research
- Siragusa Foundation
- Robert and Clarice Smith & Abigail Van Buren Alzheimer's Disease Research Foundation
- Digiovanni Sundry Fund
- ATA
- Project ALS
- Angel Fund
- Italian Ministry of Health [RF-2009-1473856]
- European Commission
- FRAXA Research Foundation
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A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ ALS). RNA of the expanded repeat (r(GGGGCC)(exp)) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing c9RAN proteins.'' Since neutralizing r(GGGGCC) exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC) exp. Chemical and enzymatic probing of r(GGGGCC) 8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC) exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC) 66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RANproteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)(exp)-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)(exp).
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