Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection

Abstract

The paraspeckle is a disease-relevant biomolecular condensate assembled from long non-coding RNA (lncRNA) NEAT1_2 ribonucleoprotein particles. Paraspeckle biogenesis is suppressed in normal tissues, yet it can be rapidly upregulated under stress. Here we demonstrate that a neurodegeneration-linked RNA-binding protein TDP-43 inhibits NEAT1_2 ribonucleoprotein particle condensation into the paraspeckle, in a concentration-dependent manner, which requires its intact polymerization and RNA binding. This effect is counterbalanced by core paraspeckle proteins such as FUS. Below disruptive concentrations, TDP-43 can be recruited into paraspeckles, forming non-liquid clusters. Under stress, TDP-43 sequestration into de novo nuclear condensates alleviates paraspeckle suppression and increases their dynamism. NEAT1_2 middle-part and 3′-end UG repeats mediate paraspeckle regulation by TDP-43 cotranscriptionally and post assembly, respectively. The deletion of the 3′-end UG repeat increases paraspeckle stability and cytoprotection in stressed human neurons. Consistently, longer 3′-end UG repeats are linked to shorter survival in the neurodegenerative disease amyotrophic lateral sclerosis. Thus, TDP-43 is a critical regulator of paraspeckle condensates linked to cytoprotection.

Metadata

Item Type:	Article
Authors/Creators:	Hodgson, R.E. Huang, W.-P. Lang, R. Kumar, V. An, H. Stender, E.G.P. Chalakova, Z.P. Driver, M.D. https://orcid.org/0000-0002-8329-888X Sanchez Avila, A. Ellis, B.C.S. Day, E. Rayment, J.A. Baeg, K. https://orcid.org/0000-0002-9733-1839 Strange, A. Moll, T. Wright, G.S.A. https://orcid.org/0000-0002-3756-9634 van Vugt, J.J.F.A. https://orcid.org/0000-0002-4161-4004 van Damme, P. Corcia, P. Couratier, P. Vourc’h, P. Hardiman, O. McLaughin, R. Gotkine, M. Lerner, Y. Yehuda, S. Drory, V. Ticozzi, N. Silani, V. Veldink, J.H. van den Berg, L.H. de Carvalho, M. Salas, T. Mora Pardina, J.S. Povedano, M. Andersen, P. Weber, M. Başak, N.A. Al-Chalabi, A. Shaw, C. Shaw, P.J. https://orcid.org/0000-0002-8925-2567 Morrison, K.E. Landers, J.E. Glass, J.D. Dalgard, C.L. van Vugt, J.J.F.A. Cooper-Knock, J. Allen, S.P. Locker, N. Pitout, I. Fletcher, S. https://orcid.org/0000-0002-8632-641X Onck, P.R. https://orcid.org/0000-0001-5632-9727 Duss, O. https://orcid.org/0000-0003-0929-3471 Cooper-Knock, J. https://orcid.org/0000-0002-0873-8689 Shelkovnikova, T.A. https://orcid.org/0000-0003-1367-5309
Copyright, Publisher and Additional Information:	© The Author(s) 2026. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Long non-coding RNAs; Mechanisms of disease; Nuclear organization
Dates:	Submitted: 3 March 2025 Accepted: 26 January 2026 Published (online): 18 March 2026 Published: April 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/V014110/1 MEDICAL RESEARCH COUNCIL MR/W028522/1 UK RESEARCH AND INNOVATION MR/W004615/1 BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/X018393/1
Date Deposited:	24 Mar 2026 17:05
Last Modified:	15 May 2026 11:09
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41556-026-01895-y
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:239449

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Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection

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