@article{12bfe540bce14d8cb591fd92aec34867,
title = "Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS",
abstract = "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 aquadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RANtranslation 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) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALStherapeutic and suggest that c9RAN proteins couldpotentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.",
author = "Zhaoming Su and Yongjie Zhang and Gendron, {Tania F.} and Bauer, {Peter O.} and Jeannie Chew and Yang, {Wang Yong} and Erik Fostvedt and Karen Jansen-West and Belzil, {Veronique V.} and Pamela Desaro and Amelia Johnston and Karen Overstreet and Oh, {Seok Yoon} and Todd, {Peter K.} and Berry, {James D.} and Cudkowicz, {Merit E.} and Boeve, {Bradley F.} and Dennis Dickson and Floeter, {Mary Kay} and Traynor, {Bryan J.} and Claudia Morelli and Antonia Ratti and Vincenzo Silani and Rosa Rademakers and Brown, {Robert H.} and Rothstein, {Jeffrey D.} and Boylan, {Kevin B.} and Leonard Petrucelli and Disney, {Matthew D.}",
note = "Funding Information: We are grateful to patients who donated CSF, skin samples, and postmortem tissue. We acknowledge Lillian Daughrity, Luc Pregent, and Mary Davis for technical support, Dr. Xiangming Kong for help with 1D 1 H NMR experiments. This work was supported by the National Institutes of Health (NIH)/National Institute on Aging (R01GM097455 [M.D.D.]; R01AG026251 [L.P.]); NIH/National Institute of Neurological Disorders and Stroke (R21NS074121 [K.B.B., T.F.G.], R21NS079807 [Y.Z.], R21NS084528 [L.P.], R01NS088689 [R.H.B., L.P.], R01NS063964 [L.P.]; R01NS077402 [L.P.]; R01NS050557 [R.H.B.]; ARRA Award RC2-NS070-342 [R.H.B.], P01NS084974 [L.P., D.D., R.R., K.B.B.]); National Institute of Environmental Health Services (R01 ES20395 [L.P.]); Department of Defense (ALSRP AL130125 [L.P., M.D.D.]); the Intramural Program of the NIH, the National Institute on Aging (Z01-AG000949-02 [B.J.T.]), and the National Institute of Neurological Disorders and Stroke (Z01 NS002976-16 to M.F.K. and B.J.T.); Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Regenerative Medicine (P.O.B.), Mayo Clinic Center for Individualized Medicine (T.F.G., L.P., K.B.B.), ALS Association (K.B.B., P.O.B., L.P., T.F.G., Y.Z., and M.E.D.), Alzheimer{\textquoteright}s Association (Y.Z.), Robert Packard Center for ALS Research at Johns Hopkins (L.P., J.D.R.), Target ALS (L.P., M.D.D.), Canadian Institutes of Health Research (V.V.B.), Siragusa Foundation (V.V.B.), Robert and Clarice Smith & Abigail Van Buren Alzheimer{\textquoteright}s Disease Research Foundation (V.V.B.), Digiovanni Sundry Fund (M.E.D.), ATA (M.E.D.), Project ALS (R.H.B.), Angel Fund (R.H.B.), AriSLA cofinanced with support of {\textquoteleft}5x1000{\textquoteright}-Healthcare research of the Italian Ministry of Health (grants EXOMEFALS 2009 [V.S.] and NOVALS 2012 [V.S.]), the Italian Ministry of Health (RF-2009-1473856 [C.M., A.R., V.S.]), and the European Commission (JNPD SOPHIA and STRENGTH [C.M., A.R., V.S.]). Z.S. and V.B. are Milton Safenowitz Postdoctoral Fellows funded by the ALS Association. W-Y.Y is a FRAXA Postdoctoral Fellow funded by FRAXA Research Foundation. Antibodies to c9RAN proteins have been licensed to a commercial entity. R.R. holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",
year = "2014",
month = sep,
day = "3",
doi = "10.1016/j.neuron.2014.07.041",
language = "English (US)",
volume = "83",
pages = "1043--1050",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}