title: Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons.
abstract: Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2+-mediated cell death signals may be a therapeutic strategy for ALS.
authors.affiliation: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Neurology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Aizawa
authors.affiliation: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Teramoto
authors.affiliation: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Akamatsu
authors.affiliation: Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Clinical Research Center for Medicine, International University of Health and Welfare, 6-1-14 Konodai, Ichikawa, Chiba 272-0827, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D022022:Nuclear Pore / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010766:Phosphorylation; D012319:RNA Polymerase II / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: D000243:Adenosine Deaminase; D002118:Calcium; D002154:Calpain; D004268:DNA-Binding Proteins; D028861:Nuclear Pore Complex Proteins; D012319:RNA Polymerase II; D016601:RNA-Binding Proteins; D018091:Receptors, AMPA; D028901:alpha Karyopherins; C527077:KPNA1 protein, mouse; C510282:NUP62 protein, mouse; C578077:Tardbp protein, mouse; C000595151:ADAR2 protein, mouse