Open AccessNuclear RNA foci from C9ORF72 expansion mutation form paraspeckle-like bodies
Author(s) -
Ana Bajc Česnik,
Simona Darovic,
Sonja Prpar Mihevc,
Maja Štalekar,
Mirjana Malnar,
Helena Motaln,
YounBok Lee,
Julija Mazej,
Jure Pohleven,
Markus Grosch,
Miha Modic,
Marko Fonović,
Boris Turk,
Micha Drukker,
Christopher E. Shaw,
Boris Rogelj
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.224303
Subject(s) - biology , rna , trinucleotide repeat expansion , c9orf72 , rna binding protein , microbiology and biotechnology , gene knockdown , genetics , gene , allele
The GGGGCC (G4C2) repeat expansion mutation in 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 (G4C2)n repeat RNA predominantly associates with essential paraspeckle proteins SFPQ, NONO, RBM14, FUS and hnRNPH and co-localizes 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 (G4C2)n RNA foci. Overexpression of (G4C2)72 RNA results in their increased number and co-localization with SFPQ-stained nuclear bodies. These paraspeckle-like (G4C2)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 (G4C2)n RNA foci. In conclusion, (G4C2)n RNA foci have characteristics of paraspeckles, which suggests that both RNA foci and paraspeckles play role in FTD and ALS and implies approaches for regulation of their formation.