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Česnik, A.B.* ; Darovic, S.* ; Mihevc, S.P.* ; Štalekar, M.* ; Malnar, M.* ; Motaln, H.* ; Lee, Y.B.* ; Mazej, J.* ; Pohleven, J.* ; Grosch, M. ; Modic, M. ; Fonovič, M.* ; Turk, B.* ; Drukker, M. ; Shaw, C.E.* ; Rogelj, B.*

Nuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies.

J. Cell Sci. 132:jcs224303 (2019)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
The GGGGCC (G(4)C(2)) repeat expansion mutation in the C9ORF72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Transcription of the repeat and formation of nuclear RNA foci, which sequester specific RNA-binding proteins, is one of the possible pathological mechanisms. Here, we show that (G(4)C(2))(n) repeat RNA predominantly associates with essential paraspeckle proteins SFPQ, NONO, RBM14, FUS and hnRNPH and colocalizes with known paraspeckle-associated RNA hLinc-p21. As formation of paraspeckles in motor neurons has been associated with early phases of ALS, we investigated the extent of similarity between paraspeckles and (G(4)C(2))(n) RNA foci. Overexpression of (G(4)C(2))(72) RNA results in their increased number and colocalization with SFPQ-stained nuclear bodies. These paraspeckle-like (G(4)C(2))(72) RNA foci form independently of the known paraspeckle scaffold, the long non-coding RNA NEAT1. Moreover, the knockdown of SFPQ protein in C9ORF72 expansion mutation-positive fibroblasts significantly reduces the number of (G(4)C(2))(n) RNA foci. In conclusion, (G(4)C(2))(n) RNA foci have characteristics of paraspeckles, which suggests that both RNA foci and paraspeckles play roles in FTD and ALS, and implies approaches for regulation of their formation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Paraspeckles ; C9orf72 ; Sfpq ; Rna Foci ; Neat1; Long Noncoding Rna; Amyotrophic-lateral-sclerosis; Dipeptide-repeat Proteins; Hexanucleotide Repeat; Ggggcc Repeat; Frontotemporal Dementia; Antisense Transcripts; Binding Proteins; Messenger-rnas; Sense
Language
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0021-9533
e-ISSN 1477-9137
Journal Journal of Cell Science
Quellenangaben Volume: 132, Issue: 5, Pages: , Article Number: jcs224303 Supplement: ,
Publisher Company of Biologists
Publishing Place Cambridge
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Stem Cell and Neuroscience
PSP Element(s) G-552400-001
DOI 10.1242/jcs.224303
WOS ID WOS:000461414300024
Scopus ID 85062627079
PubMed ID 30745340
Erfassungsdatum 2019-03-14
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