Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Compromised paraspeckle formation as a pathogenic factor in FUSopathies

Shelkovnikova, Tatyana, Robinson, Hannah, Troakes, C., Ninkina, Natalia and Buchman, Vladimir 2014. Compromised paraspeckle formation as a pathogenic factor in FUSopathies. Human Molecular Genetics 23 (9) , pp. 2298-2312. 10.1093/hmg/ddt622

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (2MB) | Preview

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Oxford University Press
ISSN: 0964-6906
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 5 December 2013
Last Modified: 15 Nov 2019 22:59
URI: http://orca.cf.ac.uk/id/eprint/59386

Citation Data

Cited 12 times in Google Scholar. View in Google Scholar

Cited 57 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics