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

Increased l1 retrotransposition in the neuronal genome in schizophrenia.

Author information

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.

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.

PMID:
24389010
DOI:
10.1016/j.neuron.2013.10.053
[Indexed for MEDLINE]
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