Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, Ostrow LW, Rothstein JD, Troncoso JC, Ranum LP. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E4968-77. Epub 2013 Nov 18 PubMed.
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Mayo Clinic Jacksonville
In this elegant study, the Ranum group provides novel insight into the presence of antisense and sense transcripts of the C9ORF72 repeat expansion, and RAN translation thereof. Through the use of antibodies toward the repeat motifs of RAN proteins, as well as antibodies against their corresponding unique C-terminal regions, the group confirmed that six C9ORF72 RAN proteins (GPS, GRS, GAS, PAAS, PRAS, GPAS) form aggregates in c9ALS brain, with GPS/AS inclusions also being present in spinal cord motor neurons. Of interest, their studies reveal that the majority of GP-repeat inclusions derive from the antisense transcript, raising the question as to whether sense and antisense transcripts are differentially prone to foci formation or RAN translation. Perhaps most exciting of all, this study provides the first evidence that C9ORF72 RAN proteins are toxic to cells. Future studies examining the toxicity of individual RAN proteins, and the mechanisms by which they cause cell death, will shed much-needed light on the involvement of RAN translation in the pathogenesis of c9FTD/ALS.
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