Increased l1 retrotransposition in the neuronal genome in schizophrenia

Miki Bundo; Manabu Toyoshima; Yohei Okada; Wado Akamatsu; Junko Ueda; Taeko Nemoto-Miyauchi; Fumiko Sunaga; Michihiro Toritsuka; Daisuke Ikawa; Akiyoshi Kakita; Motoichiro Kato; Kiyoto Kasai; Toshifumi Kishimoto; Hiroyuki Nawa; Hideyuki Okano; Takeo Yoshikawa; Tadafumi Kato; Kazuya Iwamoto

doi:10.1016/j.neuron.2013.10.053

Increased l1 retrotransposition in the neuronal genome in schizophrenia

Neuron. 2014 Jan 22;81(2):306-13. doi: 10.1016/j.neuron.2013.10.053. Epub 2014 Jan 2.

Authors

Miki Bundo¹, Manabu Toyoshima², Yohei Okada³, Wado Akamatsu³, Junko Ueda⁴, Taeko Nemoto-Miyauchi⁴, Fumiko Sunaga⁵, Michihiro Toritsuka⁶, Daisuke Ikawa⁶, Akiyoshi Kakita⁷, Motoichiro Kato⁸, Kiyoto Kasai⁹, Toshifumi Kishimoto⁶, Hiroyuki Nawa¹⁰, Hideyuki Okano³, Takeo Yoshikawa², Tadafumi Kato¹¹, Kazuya Iwamoto¹²

Affiliations

¹ 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.
² Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
³ Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁴ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
⁵ Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
⁶ Department of Psychiatry, Nara Medical University, Nara 634-8521, Japan.
⁷ Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
⁸ Department of Neuropsychiatry, Keio University School of Medicine, Tokyo 160-8582, Japan.
⁹ Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
¹⁰ Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
¹¹ Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama 351-0198, Japan. Electronic address: kato@brain.riken.jp.
¹² 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.

PMID: 24389010
DOI: 10.1016/j.neuron.2013.10.053

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

22q11 Deletion Syndrome / complications
22q11 Deletion Syndrome / genetics
22q11 Deletion Syndrome / pathology
Adult
Animals
Animals, Newborn
Cells, Cultured
DNA Copy Number Variations / genetics*
DNA Transposable Elements / genetics*
Disease Models, Animal
Endogenous Retroviruses / genetics
Endonucleases / genetics
Endonucleases / metabolism
Epidermal Growth Factor / toxicity
Female
Fibroblasts / drug effects
Gene Ontology
Genetic Predisposition to Disease
Genome / genetics
Humans
Macaca fascicularis
Male
Mice
Mice, Inbred C57BL
Middle Aged
Neurons / drug effects
Neurons / metabolism*
Phosphopyruvate Hydratase / metabolism
Pluripotent Stem Cells / drug effects
Poly I-C / toxicity
Postmortem Changes
Prefrontal Cortex / pathology*
Pregnancy
Pregnancy Proteins / genetics*
RNA-Directed DNA Polymerase / genetics
RNA-Directed DNA Polymerase / metabolism
Rett Syndrome / genetics
Risk Factors
Schizophrenia / chemically induced
Schizophrenia / genetics
Schizophrenia / pathology*
Transfection

Substances

DNA Transposable Elements
L1 ORF2 protein, human
Pregnancy Proteins
RTL1 protein, human
Epidermal Growth Factor
RNA-Directed DNA Polymerase
Endonucleases
Phosphopyruvate Hydratase
Poly I-C