TDP-43 is a master regulator of paraspeckle condensation. Hodgson, Huang et al.

The paraspeckle is a stress-inducible condensate assembled from NEAT1_2 lncRNA ribonucleoprotein particles (RNPs) by FUS protein. Paraspeckles are suppressed in normal tissues but are rapidly yet transiently upregulated under stress. We demonstrate that TDP-43 inhibits the condensation of NEAT1 RNPs into the paraspeckle via polymerisation on NEAT1_2 UG-repeats, in a concentration-dependent manner. This condensation defect can be rescued by FUS supplementation. Below the disruptive concentration, TDP-43 partitions into paraspeckles as non-liquid clusters demixed from the FUS microphase. In stressed cells, TDP-43 sequestration into de novo nuclear condensates alleviates paraspeckle suppression and increases their dynamism. NEAT1_2 middle-part UG-repeats mediate co-transcriptional TDP-43 recruitment and paraspeckle condensation control, whereas the 3’-end UG-repeat contributes to paraspeckle regulation post-assembly. ExpansionHunter analysis in ~5000 amyotrophic lateral sclerosis patients linked longer 3’-end repeats to shorter survival. Thus, TDP-43 acts as a molecular switch between paraspeckle low- and high-assembly states and fine-tunes their properties – a mechanism dysregulated in neurodegeneration.