Journal article
Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs
J Jiang, Q Zhu, TF Gendron, S Saberi, M McAlonis-Downes, A Seelman, JE Stauffer, P Jafar-nejad, K Drenner, D Schulte, S Chun, S Sun, SC Ling, B Myers, J Engelhardt, M Katz, M Baughn, O Platoshyn, M Marsala, A Watt Show all
Neuron | CELL PRESS | Published : 2016
Abstract
Hexanucleotide expansions in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Disease mechanisms were evaluated in mice expressing C9ORF72 RNAs with up to 450 GGGGCC repeats or with one or both C9orf72 alleles inactivated. Chronic 50% reduction of C9ORF72 did not provoke disease, while its absence produced splenomegaly, enlarged lymph nodes, and mild social interaction deficits, but not motor dysfunction. Hexanucleotide expansions caused age-, repeat-length-, and expression-level-dependent accumulation of RNA foci and dipeptide-repeat proteins synthesized by AUG-independent translation, accompanied by loss of hippocampal neurons, incre..
View full abstractGrants
Awarded by Mayo Clinic
Funding Acknowledgements
We thank Patrick King, Clement Ng, Cheyenne Schloffman, Marcus Maldonado, Anh Bui, and Drs. Ricardos Tabet, Kent Osborn, and Nissi Varki for their advice and technical assistance. We thank all members of D.W.C., C.L.-T., and J.R. groups and the teamat Ionis Pharmaceuticals for critical suggestions on this project. This work was supported by the ALS Association (a Neurocollaborative grant to D.W.C., grants to T.F.G. and L.P., and a Milton Safenowitz postdoctoral fellowship to Q.Z.); grants from the NIH (R01-NS088578 to J.R. and D.W.C., R01-NS087227 to C.L.-T., R21-NS089979 to T.F.G., as well as R21-NS084528, R01-NS088689, R01-NS063964, R01-NS077402, and P01-NS084974 to L.P.); the UCSD Alzheimer's Disease Research Center (to C.L.-T.); research project funding from Target ALS to C.L.-T. (13-04827), J.R. (13-44792), and L.P.; the Robert Packard Center for ALS Research at Johns Hopkins (to L.P.); the Mayo Clinic Foundation (to L.P.); a senior clinical investigatorship and a grant from FWO-Vlaanderen to P.V.D.; the Belgian Alzheimer Disease Association (SAO; to P.V.D.); and the European Union's Seventh Framework Programme FP7/2014-2019 under grant agreement no 617198 [DPR-MODELS] (to D.E.). J. J. was supported by NIH postdoctoral fellowships (T32 AG00216 and F32 NS087842). S. Sun is the recipient of career development grants from the NIH (K99 NS091538) and Target ALS. L.D.M. is employed by Janssen Pharmaceutical Companies of Johnson & Johnson. P.J., S.C., J.E., A.W., C.F.B., and F.R. are employees and D.W.C. is a consultant for Ionis Pharmaceuticals. J.R. received salary support from the University of California, San Diego. C.L.-T. and D.W.C. received salary support from the Ludwig Institute for Cancer Research.