Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
Copley KE., Mauna JC., Danielson HL., Chen Q., Ozguney B., Ngo M., Xie L., Smirnov A., Davis M., Mayne L., Linsenmeier M., Rubien JD., Bergmann CA., Portz B., Lee BL., Odeh HM., Lai L., Chang YW., Hallegger M., Ule J., Pasinelli P., Poon Y., Mittal J., Fawzi NL., Black BE., Donnelly CJ., Jensen BK., Shorter J.
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.