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bioRxiv · 10.1101/2025.03.19.643735

RGG peptide induces the disassembly of disease-relevant FUS and TDP43 condensates

Garg, M.·Vinayan, N.·Ghosh, P.·Kesavardhana, S. I.·Rajyaguru, P. I.
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Abstract

Mislocalization and cytoplasmic condensation of nuclear proteins, such as FUS and TDP43, are key features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, mechanisms governing the disassembly of these pathological condensates remain elusive. Here, we identify a disordered RGG peptide as a disassembly factor for mutant FUS and TDP43 condensates. Using yeast, mammalian cells, and in vitro assays, we observe that an RGG motif reduces condensate burden and toxicity while restoring nuclear localization and RNA regulatory defects associated with the FUS-P525L mutant. The RGG motif interacts with FUS, competitively inhibiting FUS self-association. Overall, our findings uncover a direct role for a disordered RGG motif in the disassembly of ALS-associated condensates, highlighting the possibility of a new therapeutic for post-symptomatic ALS.

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Garg, M., Vinayan, N., Ghosh, P., Kesavardhana, S. I., Rajyaguru, P. I.. 2025-03-19. RGG peptide induces the disassembly of disease-relevant FUS and TDP43 condensates. https://doi.org/10.1101/2025.03.19.643735

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