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

Hodgson, Rachel E., Huang, Wan-Ping, Lang, Ruaridh, Kumar, Vedanth, An, Haiyan and Stender, Emil G. P. 2026. Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection. Nature Cell Biology 10.1038/s41556-026-01895-y

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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.

Item Type:	Article
Date Type:	Publication
Status:	In Press
Schools:	Schools > Biosciences
Additional Information:	For full list of authors please see https://doi.org/10.1038/s41556-026-01895-y
Publisher:	Springer Science and Business Media LLC
ISSN:	1465-7392
Date of First Compliant Deposit:	23 March 2026
Date of Acceptance:	26 January 2026
Last Modified:	23 Mar 2026 10:31
URI:	https://orca.cardiff.ac.uk/id/eprint/185929

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