title: Compromised paraspeckle formation as a pathogenic factor in FUSopathies.
abstract: Paraspeckles are nuclear bodies formed by a set of specialized proteins assembled on the long non-coding RNA NEAT1; they have a role in nuclear retention of hyperedited transcripts and are associated with response to cellular stress. Fused in sarcoma (FUS) protein, linked to a number of neurodegenerative disorders, is an essential paraspeckle component. We have shown that its recruitment to these nuclear structures is mediated by the N-terminal region and requires prion-like activity. FUS interacts with p54nrb/NONO, a major constituent of paraspeckles, in an RNA-dependent manner and responds in the same way as other paraspeckle proteins to alterations in cellular homeostasis such as changes in transcription rates or levels of protein methylation. FUS also regulates NEAT1 levels and paraspeckle formation in cultured cells, and FUS deficiency leads to loss of paraspeckles. Pathological gain-of-function FUS mutations might be expected to affect paraspeckle function in human diseases because mislocalized amyotrophic lateral sclerosis (ALS)-linked FUS variants sequester other paraspeckle proteins into aggregates formed in cultured cells and into neuronal inclusions in a transgenic mouse model of FUSopathy. Furthermore, we detected abundant p54nrb/NONO-positive inclusions in motor neurons of patients with familial forms of ALS caused by FUS mutations, but not in other ALS cases. Our results suggest that both loss and gain of FUS function can trigger disruption of paraspeckle assembly, which may impair protective responses in neurons and thereby contribute to the pathogenesis of FUSopathies.
authors: School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors: Tatyana A
authors: TA
authors: Shelkovnikova
authors: Hannah K
authors: HK
authors: Robinson
authors: Claire
authors: C
authors: Troakes
authors: Natalia
authors: N
authors: Ninkina
authors: Vladimir L
authors: VL
authors: Buchman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D062085:RNA, Long Noncoding / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000378:metabolism*
chemical_list: C577276:NEAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; D034702:RNA-Binding Protein FUS