Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.
Publication/Presentation Date
5-7-2026
Abstract
Aberrant aggregation of the prion-like RNA binding protein TDP-43 drives several fatal neurodegenerative proteinopathies, including amyotrophic lateral sclerosis (ALS). In this work, we define how short, specific RNAs solubilize TDP-43. These short RNAs engage and stabilize the TDP-43 RNA recognition motifs, which allosterically destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregation-resistant conformers. Sequence-space mining identified short RNA chaperones with enhanced activity against TDP-43 and disease-linked variants. Enhanced short RNA chaperones mitigated aberrant TDP-43 phenotypes in optogenetic models and in ALS patient-derived and control motor neurons. In mice with cytoplasmic TDP-43 aggregation and motor neuron loss, an enhanced short RNA chaperone reduced pathological aggregation, restored TDP-43 function, and conferred neuroprotection. These results define a mechanistic and therapeutic framework for RNA-based strategies to counter TDP-43 proteinopathies.
Volume
392
Issue
6798
First Page
3301
Last Page
3301
ISSN
1095-9203
Published In/Presented At
Copley, K. E., Mauna, J. C., Danielson, H. L., Chen, Q., Ozguney, B., Ngo, M., Xie, L., Smirnov, A., Davis, M., Mayne, L., Linsenmeier, M., Rubien, J. D., Bergmann, C. A., Portz, B., Lee, B. L., Odeh, H. M., Lai, L., Chang, Y. W., Hallegger, M., Ule, J., … Shorter, J. (2026). Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration. Science (New York, N.Y.), 392(6798), eadv3301. https://doi.org/10.1126/science.adv3301
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
42096556
Department(s)
Administration and Leadership
Document Type
Article