Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
- Katie E. Copley
- Jocelyn C. Mauna
- Helen L. Danielson
- Qizan Chen
- Busra Ozguney
- Marilyn Ngo
- Longxin Xie
- Ashleigh Smirnov
- Matt Davis
- Leland Mayne
- Miriam Linsenmeier
- Jack D. Rubien
- Cristian A. Bergmann
- Bede Portz
- Bo Lim Lee
- Hana M. Odeh
- Longsheng Lai
- Yi-Wei Chang
- Martina Hallegger
- Jernej Ule
- Piera Pasinelli
- Yan Poon
- Jeetain Mittal
- Nicolas L. Fawzi
- Ben E. Black
- Christopher J. Donnelly
- Brigid K. Jensen
- James Shorter
2026-05-07
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.