title: Increased l1 retrotransposition in the neuronal genome in schizophrenia.
abstract: Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.
authors.affiliation: Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Bundo
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Toyoshima
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Wado
authors.initials: W
authors.lastname: Akamatsu
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Ueda
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Nemoto-Miyauchi
authors.affiliation: Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sunaga
authors.affiliation: Department of Psychiatry, Nara Medical University, Nara 634-8521, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Toritsuka
authors.affiliation: Department of Psychiatry, Nara Medical University, Nara 634-8521, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ikawa
authors.affiliation: Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Motoichiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kasai
authors.affiliation: Department of Psychiatry, Nara Medical University, Nara 634-8521, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nawa
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan. Electronic address: kato@brain.riken.jp.
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan. Electronic address: kaziwamoto-tky@umin.ac.jp.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Iwamoto
mesh_terms: D058165:22q11 Deletion Syndrome / Q000150:complications / Q000235:genetics / Q000473:pathology; D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D056915:DNA Copy Number Variations / Q000235:genetics*; D004251:DNA Transposable Elements / Q000235:genetics*; D004195:Disease Models, Animal; D020077:Endogenous Retroviruses / Q000235:genetics; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000633:toxicity; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D063990:Gene Ontology; D020022:Genetic Predisposition to Disease; D016678:Genome / Q000235:genetics; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000187:drug effects; D011070:Poly I-C / Q000633:toxicity; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000473:pathology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D014162:Transfection
chemical_list: D004251:DNA Transposable Elements; C494024:L1 ORF2 protein, human; D011257:Pregnancy Proteins; C579465:RTL1 protein, human; D004815:Epidermal Growth Factor; D012194:RNA-Directed DNA Polymerase; D004720:Endonucleases; D010751:Phosphopyruvate Hydratase; D011070:Poly I-C