Science on Target: Q2 2026 New in Science
July 8, 2026 Amy Easton
Short RNA Chaperones Mediate TDP-43 Aggregation Potential
Katie Copley (Corsalex Fellowship Awardee), alongside Target-ALS-funded investigators Christopher Donnelly and James Shorter, recently published a study in the March edition of Science that investigated how short RNA chaperones mediate TDP-43 condensation and aggregation, and whether they represent a viable therapeutic.
The key findings by Copley et al. indicate that RNA recognition motifs (RRMs) 1 and 2 are critical domains of TDP-43 with high aggregation propensity, and short RNA chaperones can engage the RRMs and attenuate TDP-43 aggregation. Additionally, the prion-like domain (PrLD) of TDP-43 was shown to impair the interaction between the RRMs and the short RNA chaperones, suggesting that the PrLD may play a role in creating RNA-deficient and aggregation-prone TDP-43. While the early iterations of these short RNA chaperones showed promise in preventing TDP-43 aggregation in some ALS/FTD-linked TDP-43 mutations, lysine acetylation of TDP-43 reduced short RNA chaperone efficacy. Copley et al. redesigned their short RNA chaperones by replacing the middle of the RNA sequence with (UG)4-repeats, thereby increasing binding with TDP-43 despite acetylation and improving efficacy.
Using their short RNA chaperones as a model, the team mined for other RNAs based on natural TDP-43 binding parameters. MALAT1 short RNA chaperone, Malat1_start, emerged as an early therapeutic candidate, showing effectiveness in solubilizing TDP-43 and reducing inclusion size and cytoplasmic puncta, restoring nuclear localization, and reducing cryptic splicing. In vivo assays confirmed that Malat1_start colocalized with TDP-43, confirming target engagement, and reduced neurodegeneration in the spinal cord.
Although Copley et al. evaluated the therapeutic potential of short chaperone RNAs to ameliorate TDP-43 aggregation using preliminary in vitro and in vivo models of TDP-43 aggregation, further validation will be necessary in other in vivo and in vitro models of ALS and TDP-43 proteinopathy. Critically, will Malat1_start efficacy prove corroborated in other in vivo models, such as Biospective’s “Low Dox” rNLS8 model, display off-target effects or interact with other proteins, and will other proteoforms of TDP-43 unexpectedly impact efficacy?
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