puc-header

TDP-43 is a Master Regulator of Paraspeckle Condensation

42 Pages Posted: 20 Feb 2024 Publication Status: Review Complete

See all articles by Rachel Hodgson

Rachel Hodgson

University of Sheffield

Wan-Ping Huang

University of Sheffield

Vedanth Kumar

University of Sheffield

Haiyan An

Cardiff University

Zhaklin Chalakova

University of Sheffield

Jessica Rayment

University of Sheffield

Brittany C.S. Ellis

University of Sheffield

Emil G.P. Stender

Fida Biosystems ApS

Joke J.F.A. van Vugt

Utrecht University - University Medical Center (Utrecht)

Project MinE ALS Sequencing Consortium

Independent

Nicolas Locker

The Pirbright Institute

Ianthe Pitout

Murdoch University

Sue Fletcher

Murdoch University

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN)

Tatyana Shelkovnikova

University of Sheffield

More...

Abstract

The paraspeckle is a stress-inducible membraneless organelle (MLO) assembled on an architectural lncRNA, NEAT1_2. Paraspeckles are widely suppressed in normal tissues but are rapidly yet transiently upregulated under stress; how this tight control is achieved is not fully understood. This MLO is dysregulated in multiple human diseases, from cancer to neurodegeneration. Here we demonstrate that TDP-43 cooperates with FUS to regulate the spectrum of NEAT1_2/paraspeckle assemblies. We find that TDP-43 disperses paraspeckles when in excess, in an RNA-binding dependent manner, and this phenotype can be replicated using in vitro FUS condensates and rescued by FUS supplementation. In stressed cells, TDP-43 is depleted from the nucleoplasm via its sequestration into de novo nuclear condensates, promoting paraspeckle assembly. In TDP-43 sufficient cells, paraspeckle suppression can be bypassed via TDP-43 condensation on NEAT1_2 UG repeats and microphase separation with FUS. TDP-43-containing and -depleted paraspeckles have different properties, with the latter being more dynamic and less prone to form clusters. Genetic analysis in a cohort of ~8000 individuals revealed that longer NEAT1_2 UG repeats associated with paraspeckle suppression positively correlate with disease severity in a neurodegenerative disease amyotrophic lateral sclerosis (ALS). To conclude, we demonstrate that TDP-43 acts as a molecular switch between the paraspeckle low- and high-assembly states and fine-tunes their properties via repeat-RNA binding, sub-MLO condensation and cross-MLO shuttling – a mechanism dysregulated in neurodegeneration.

Note:

Funding Information: The work was supported by the UKRI Future Leaders Fellowship (MR/W004615/1), MRC (MR/W028522/1) and BBSRC (BB/V014110/1 and BB/V014528/1) grants, MND Association grant (Shelkovnikova/Oct17/968-799) and MND Scotland PhD studentship (2022/MNDS/PHD/8045SHEL).

Conflict of Interests: E.G.P.S. is an employee of Fida Biosystems. All other authors have no conflicting interests to declare.

Ethical Approval: All participants gave written informed consent. The institutional review board of the University Medical Center Utrecht approved this study.

Keywords: TDP-43, paraspeckle, NEAT1, FUS, UG-repeat, ALS, membraneless organelle, condensate, stress response

Suggested Citation

Hodgson, Rachel and Huang, Wan-Ping and Kumar, Vedanth and An, Haiyan and Chalakova, Zhaklin and Rayment, Jessica and Ellis, Brittany C.S. and Stender, Emil G.P. and van Vugt, Joke J.F.A. and Sequencing Consortium, Project MinE ALS and Locker, Nicolas and Pitout, Ianthe and Fletcher, Sue and Cooper-Knock, Johnathan and Shelkovnikova, Tatyana, TDP-43 is a Master Regulator of Paraspeckle Condensation. Available at SSRN: https://ssrn.com/abstract=4721338 or http://dx.doi.org/10.2139/ssrn.4721338
This version of the paper has not been formally peer reviewed.

Rachel Hodgson

University of Sheffield ( email )

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Wan-Ping Huang

University of Sheffield ( email )

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Vedanth Kumar

University of Sheffield ( email )

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Haiyan An

Cardiff University ( email )

Aberconway Building
Colum Drive
Cardiff, CF10 3EU
United Kingdom

Zhaklin Chalakova

University of Sheffield ( email )

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Jessica Rayment

University of Sheffield ( email )

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Brittany C.S. Ellis

University of Sheffield ( email )

17 Mappin Street
Sheffield, S1 4DT
United Kingdom

Emil G.P. Stender

Fida Biosystems ApS ( email )

Joke J.F.A. Van Vugt

Utrecht University - University Medical Center (Utrecht) ( email )

Nicolas Locker

The Pirbright Institute ( email )

Ianthe Pitout

Murdoch University ( email )

South Street
Murdoch 6150, 6105
Australia

Sue Fletcher

Murdoch University ( email )

South Street
Murdoch 6150, 6105
Australia

Johnathan Cooper-Knock

University of Sheffield - Sheffield Institute for Translational Neuroscience (SITraN) ( email )

385a Glossop Road
Sheffield
United Kingdom

Tatyana Shelkovnikova (Contact Author)

University of Sheffield ( email )

Click here to go to Cell.com

Paper statistics

Downloads
22
Abstract Views
169
PlumX Metrics