Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
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.
Cold atmospheric plasma treatment of FlpIn SH-SY5Y cells with an inducible expression of G3BP1 results in stress granule assembly resembling a cellular oxidative stress response that has been shown to be eIF2α-signaling dependent and inhibited by an ISRIB inhibitor.
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