TDP ‐43 binds and transports G ‐quadruplex‐containing m RNA s into neurites for local translation

Growth and differentiation of the neurites depends on long‐distance transport of a specific set of m RNA s to restricted area and their local translation. Here, we found that a TAR DNA ‐binding protein of 43 kDa in size ( TDP ‐43) plays an essential role in intracellular transport of m RNA . For identification of target RNA s recognized by TDP ‐43, we purified TDP ‐43 in soluble dimer form and subjected to in vitro systematic evolution of ligands by exponential enrichment ( SELEX ) screening. All the TDP ‐43‐bound RNA s were found to contain G ‐quadruplex ( G 4). Using a double‐fluorescent probe system, G 4‐containing RNA s were found to be transported, together with TDP ‐43, into the distal neurites. Two lines of evidence indicated that loss of function of TDP ‐43 results in the neurodegenerative disorder: (i) amyotrophic lateral sclerosis ( ALS )‐linked mutant TDP ‐43 M337V lacks the activity of binding and transport of G4‐containing m RNA s; and (ii) RNA containing G 4‐forming GGGGCC repeat expansion from the ALS ‐linked C9orf72 gene absorbs TDP ‐43, thereby reducing the intracellular pool of functional TDP ‐43. Taken together, we propose that TDP ‐43 within neurons plays an essential role of m RNA transport into distal neurites for local translation, and thus, dysfunctions of TDP ‐43 cause neural diseases such as ALS and frontotemporal lobar degeneration.