Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study
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Three main mechanisms are thought to contribute to neurodegeneration in C9ORF72 amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD): toxicity from transcribed expanded repeat RNAs, toxicity from RAN-translated dipeptide repeat proteins (DPRs), and loss of C9ORF72 protein function [4, 5, 9, 11, 12, 18]. Sense and antisense RNA foci have both been consistently observed in C9-ALS/FTD neuropathology [1, 3, 5, 8, 9, 18] and hypothesized to cause neurodegeneration by sequestering critical RNA-binding proteins [2, 6]. Antisense, but not sense RNA foci have been shown to correlate with mislocalization of TDP-43, a signature protein of ALS and frontal–temporal lobar degeneration (FTLD) . A unique circumferential studding of nucleoli by antisense RNA foci was observed in a case report of two C9-FTLD cases  and recently re-discussed with two additional cases . Understanding the relative contributions from sense and antisense strands to pathogenesis is...
This research was supported by grants from ALS Association (5356S3), Target ALS (20134792), National Institute of Neurological Diseases and Stroke (NIH R01NS088578 and NS047101), and Pam Golden. OAA is supported by National Science Foundation Graduate Research Fellowship (DGE-1650112). TO is supported by NINDS CReATe Consortium (U54NS092091). Len Petrucelli provided extra sense probe for FISH. We thank the patients and their families for their generous contribution to this research.
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Conflict of interest
The authors declare that they have no conflict of interest.
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