Short RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration.
Abstract:
Aberrant aggregation of the prion-like, RNA-binding protein TDP-43 underlies
several debilitating neurodegenerative proteinopathies, including amyotrophic lateral sclerosis
(ALS). Here, we define how short, specific RNAs antagonize TDP-43 aggregation. Short,
specific RNAs engage and stabilize the TDP-43 RNA-recognition motifs, which allosterically
destabilizes a conserved helical region in the prion-like domain, thereby promoting aggregationresistant conformers. By mining sequence space, we uncover short RNAs with enhanced activity
against TDP-43 and diverse disease-linked variants. The solubilizing activity of enhanced short
RNA chaperones corrects aberrant TDP-43 phenotypes in optogenetic models and ALS patientderived neurons. Remarkably, an enhanced short RNA chaperone mitigates TDP-43
proteinopathy and neurodegeneration in mice. Our studies reveal mechanisms of short RNA
chaperones and pave the way for the development of short RNA therapeutics for fatal TDP-43
proteinopathies.
