Functional TDP-43 amyloids bind sarcomeric mRNA to direct skeletal muscle formation

Cytoplasmic aggregates of TDP-43 are found in neuronal and skeletal muscle diseases yet it is not understood how these protein aggregates relate to the biological function of TDP-43. By examining normal skeletal muscle formation, we discovered TDP-43 redistributes from the nucleus into the cytoplasm and forms higher-ordered aggregates. These skeletal muscle TDP-43 aggregates adopt an amyloid-like structure capable of binding RNA. In skeletal muscle, TDP-43 binds UG-rich, sarcomeric mRNAs and oligomerizes on these long mRNA transcripts facilitating amyloid formation. Tissue specific genetic deletion of TDP-43 in skeletal muscle disrupts the formation and maintenance of the sarcomere and mislocalizes sarcomeric mRNAs. Thus, cytoplasmic, amyloid-like TDP-43 aggregates that traffic mRNAs could serve as a precursor to pathological TDP-43 aggregates common in degenerative neuromuscular disease. eCLIP-seq in mouse C2C12 cells