title: TDP-43 binds and transports G-quadruplex-containing mRNAs into neurites for local translation.
abstract: Growth and differentiation of the neurites depends on long-distance transport of a specific set of mRNAs 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 mRNA. For identification of target RNAs 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 RNAs were found to contain G-quadruplex (G4). Using a double-fluorescent probe system, G4-containing RNAs 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-43M337V lacks the activity of binding and transport of G4-containing mRNAs; and (ii) RNA containing G4-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 mRNA transport into distal neurites for local translation, and thus, dysfunctions of TDP-43 cause neural diseases such as ALS and frontotemporal lobar degeneration.
authors.affiliation: Research Center for Micro-Nano Technology, University of Hosei, Midori-cho 3-11-15, Koganei, Tokyo, 184-0003, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiguro
authors.affiliation: Section of Cell Biology and Pathology, Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Morioka 7-430, Obu, Aichi, 474-8511, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kimura
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Yayoi 2-11-16, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Molecular and Developmental Biology, Institute of Medical Science, The University of Tokyo, Shirokane-dai 4-6-1, Minatoku-ku, Tokyo, 108-8639, Japan.
authors.forename: Sumiko
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Research Center for Micro-Nano Technology, University of Hosei, Midori-cho 3-11-15, Koganei, Tokyo, 184-0003, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishihama
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism / Q000473:pathology; D054856:G-Quadruplexes; D006801:Humans; D016501:Neurites / Q000378:metabolism*; D014176:Protein Biosynthesis; D034443:RNA Transport; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D052156:SELEX Aptamer Technique
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000598624:TARDBP protein, human