title: Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons-especially neurons with mislocalized TDP-43-the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan Center for Transdisciplinary Research, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Koyama
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugai
authors.affiliation: Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ishihara
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan Center for Transdisciplinary Research, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiga
authors.affiliation: Department of Pathology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Toyoshima
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Konno
authors.affiliation: Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirokawa
authors.affiliation: Department of Molecular Neuroscience, Resource Branch for Brain Disease Research, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yokoseki
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Department of Pathology, Center for Bioresource-based Research, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Pathology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Neurology, Clinical Neuroscience Branch, Brain Research Institute, 1-757 Asahimachi-dori, Chuo-ku, Niigata-City, Niigata 951-8585, Japan onodera@bri.niigata-u.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D003593:Cytoplasm / Q000378:metabolism / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C000598624:TARDBP protein, human