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Circular RNA aptamers as superb sub-stoichiometric chaperones of TDP-43 condensation
bioRxiv · · Preprint · Open access
Wu, Luan + 13 more
Abstract ↗AI summary
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Two circular RNA aptamers, circT3 and its 116-nt derivative circT3-M3, suppress TAR DNA-binding protein 43 (TDP-43) condensation with exceptionally potent sub-stoichiometric activity.
- Why it matters: Antagonizing pathological TDP-43 states without disrupting normal function is difficult, and condensation linked to amyotrophic lateral sclerosis and frontotemporal dementia remains a key therapeutic target.
- What they did: The authors show the Capts bind TDP-43 reversibly and iteratively through residues in the RRM1 domain, promoting rapid multiple RRM1-dependent homomeric assembly events that keep TDP-43 soluble.
- The result: In a cellular model, Capt delivery rescues TDP-43-dependent aberrant splicing, and in vivo it partially ameliorates TDP-43 proteinopathy-driven motor dysfunction, supporting Capts as next-generation RNA therapeutics.
The findingWhy it mattersWhat they didThe result
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