title: Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations.
abstract: The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Nael H
authors: NH
authors: Alami
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Rebecca B
authors: RB
authors: Smith
authors: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
authors: Monica A
authors: MA
authors: Carrasco
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
authors: Luis A
authors: LA
authors: Williams
authors: Department of Ophthalmology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
authors: Christina S
authors: CS
authors: Winborn
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.|Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Steve S W
authors: SSW
authors: Han
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
authors: Evangelos
authors: E
authors: Kiskinis
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Brett
authors: B
authors: Winborn
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Brian D
authors: BD
authors: Freibaum
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Anderson
authors: A
authors: Kanagaraj
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Alison J
authors: AJ
authors: Clare
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: Nisha M
authors: NM
authors: Badders
authors: Euan MacDonald Centre for Motor Neurone Disease Research, Medical Research Council Centre for Regenerative Medicine, Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors: Bilada
authors: B
authors: Bilican
authors: Department of Ophthalmology, University of Tennessee Health Sciences Center, Memphis, TN 38163, USA.
authors: Edward
authors: E
authors: Chaum
authors: Euan MacDonald Centre for Motor Neurone Disease Research, Medical Research Council Centre for Regenerative Medicine, Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK.
authors: Siddharthan
authors: S
authors: Chandran
authors: Departments of Clinical Neuroscience and Neurodegeneration and Brain Injury, King's College London and King's Health Partners, MRC Centre for Neurodegeneration Research, London SE5 8AF, UK.
authors: Christopher E
authors: CE
authors: Shaw
authors: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138.
authors: Kevin C
authors: KC
authors: Eggan
authors: Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
authors: Tom
authors: T
authors: Maniatis
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors: J Paul
authors: JP
authors: Taylor
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008164:Luminescent Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C492187:Stau1 protein, mouse