Retrotransposition of Long Interspersed Element 1 Induced by Methamphetamine or Cocaine

Okudaira, Noriyuki; Ishizaka, Yukihito; Nishio, Hisahide

doi:10.1074/jbc.m114.559419

Cited by 28 publications

(26 citation statements)

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“…Ex vivo mouse brain (Maze et al., 2011) and neuronal cell line (Okudaira et al., 2014) experiments suggested increased L1 transcription and retrotransposition, respectively, occurs after cocaine exposure. Our data indicated no significant increase in relative levels of L1 mRNA in mPFC of CA individuals as compared to controls (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…It is unknown whether these CA findings would extend to other commonly abused drugs; however, the in vitro data of Okudaira et al. (2014) indicate that in neuronal cell lines, methamphetamine, but not ethanol or barbiturates, may also induce L1 retrotransposition. Moszczynska, Flack, Qiu, Muotri, and Killinger (2015) also showed that methamphetamine increased L1 expression and retrotransposition.…”

Section: Discussionmentioning

confidence: 99%

“…Given reports of transcriptional activation of L1s in brains of cocaine‐treated mice (Maze et al., 2011) and increased L1 retrotransposition in cocaine‐treated neuronal cell cultures (Okudaira, Ishizaka, & Nishio, 2014), we proposed two hypotheses for how L1 retrotransposons might influence susceptibility to CA, or its symptoms. First, certain inherited (germline L1s) or noninherited ( de novo somatic L1 retrotransposition during neurogenesis) L1 gene disruptions might predispose individuals to developing CA.…”

Section: Introductionmentioning

confidence: 95%

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Reading LINEs within the cocaine addicted brain

Doyle

Doucet-O’Hare²,

Hammond

et al. 2017

Brain and Behavior

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IntroductionLong interspersed element (LINE)‐1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine‐treated mice, and L1 retrotransposition was increased in cocaine‐treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain.MethodsPostmortem medial prefrontal cortex (mPFC) tissue from 30 CA and 30 control individuals was studied. An Alexafluor488‐labeled NeuN antibody and fluorescence activated nuclei sorting were used to separate neuronal from non‐neuronal cell nuclei. L1s and their 3' flanking sequences were amplified from neuronal and non‐neuronal genomic DNA (gDNA) using L1‐seq. L1 DNA libraries from the neuronal gDNA were sequenced on an Illumina HiSeq2000. Sequences aligned to the hg19 human genome build were analyzed for L1 insertions using custom “L1‐seq” bioinformatics programs.ResultsPreviously uncataloged L1 insertions, some validated by PCR, were detected in neurons from both CA and control brain samples. Steady‐state L1 mRNA levels in CA and control mPFC were also assessed. Gene ontology and pathway analyses were used to assess relationships between genes putatively disrupted by novel L1s in CA and control individuals. L1 insertions in CA samples were enriched in gene ontologies and pathways previously associated with CA.ConclusionsWe conclude that neurons in the mPFC harbor L1 insertions that have the potential to influence predisposition to CA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Reading LINEs within the cocaine addicted brain

Doyle

Doucet-O’Hare²,

Hammond

et al. 2017

Brain and Behavior

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“…21 Interestingly, however, fluoxetine has been shown to protect against the SIinduced defect mainly during the mitotic phase of neurogenesis, 17,37 leading us to speculate that the age-dependent L1 increase is regulated by the postmitotic step of neurogenesis. Recently, it was reported that stimulants such as methamphetamine 9,10 and cocaine, 9 or neurotransmitters such as glutamate and dopamine 10 reproducibly induced L1-RTP in neuronal cells. These observations imply that multiple environmental factors are capable of inducing L1-RTP in the brain.…”

Section: L1 Inhibition Is Linked With Psychiatric Disorders and Blockmentioning

confidence: 99%

“…2 Notably, L1 is active in neuronal precursor cells, and L1-RTP insertions provoke the expression of neuron-specific genes when their gene structures are altered by de novo L1 insertion. [3][4][5] Recent studies have identified L1-mediated somatic mosaicism in normal adult brains, 6,7 and high copy numbers of L1 were detected in the brain of a schizophrenia patient, 8 Okudaira et al recently reported that stimulants such as methamphetamine and cocaine induced L1-RTP in neuronal cells, 9,10 and Moszczynska et al demonstrated that glutamate activated L1-RTP. 10 These observations imply that L1-RTP is physiologically regulated via the axis of glutamate and the glutamate receptor and that normal brain maturation is affected by the deregulation of L1-RTP, which functions as a molecular basis of psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation

Ueno

Okamura²,

Mishina

et al. 2016

Mobile Genetic Elements

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Background: Retrotransposition of long interspersed nuclear element-1 (L1-RTP) is proposed to contribute to central nervous system (CNS) plasticity by inducing mosaicism of neuronal cells. Clinical studies have identified increased L1 copy numbers in the brains of patients with psychiatric disorders. These observations implicate that L1-RTP is important for neurogenesis and that its deregulation represents a risk factor for mental disorders. However, no supportive evidence is available for understanding the importance of L1-RTP in CNS function. Findings: To explore the physiological role of L1-RTP in CNS, we examined the L1 copy number during maturation. Interestingly, the L1 copy number increased after birth in the mouse hippocampus, but not the frontal lobe, with maximal copy numbers found in 8-week-old mice. This age-dependent L1 increase was abolished by administration of a reverse-transcriptase inhibitor, stavudine (d4T), which showed no toxic effects. Notably, the age-dependent L1 increase was attenuated by post-weaning social isolation (SI) stress, a well-known intervention for inducing psychiatric disorders in mice, or deletion of the NR2A gene that encodes a subunit of the glutamate receptor. Moreover, the negative effects of SI stress on L1-RTP were partially restored by environmental enrichment with voluntary running, but not by fluoxetine, a commonly used antipsychiatric drug. Finally, behavioral experiments revealed that learning memory was defective in d4T-treated mice, which was similarly observed in mice raised under SI stress. Conclusion: We detected the modulation of L1-RTP in the hippocampus during maturation of the CNS. In a recent study, we demonstrated that stimulants such as methamphetamine and cocaine were active in the induction of L1-RTP in neuronal cells, and previous studies have shown that NR2A-deficient mice are susceptible to mental abnormality. Herein, our data support the notion that the age-dependent modulation of L1-RTP is involved in genome differentiation in the hippocampus, and that modulation defects are linked to the development of psychiatric disorders.

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Long INterspersed element‐1 mobility as a sensor of environmental stresses

Giorgi

2020

Environ and Mol Mutagen

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Long INterspersed element (LINE-1, L1) retrotransposons are the most abundant transposable elements in the human genome, constituting approximately 17%. They move by a "copy-paste" mechanism, involving reverse transcription of an RNA intermediate and insertion of its cDNA copy at a new site in the genome. L1 retrotransposition (L1-RTP) can cause insertional mutations, alter gene expression, transduce exons, and induce epigenetic dysregulation. L1-RTP is generally repressed; however, a number of observations collected over about 15 years revealed that it can occur in response to environmental stresses. Moreover, emerging evidence indicates that L1-RTP can play a role in the onset of several neurological and oncological diseases in humans. In recent years, great attention has been paid to the exposome paradigm, which proposes that health effects of an environmental factor should be evaluated considering both cumulative environmental exposures and the endogenous processes resulting from the biological response. L1-RTP could be an endogenous process considered for this application. Here, we summarize the current understanding of environmental factors that can affect the retrotransposition of human L1 elements. Evidence indicates that L1-RTP alteration is triggered by numerous and various environmental stressors, such as chemical agents (heavy metals, carcinogens, oxidants, and drugs), physical agents (ionizing and non-ionizing radiations), and experiential factors (voluntary exercise, social isolation, maternal care, and environmental light/dark cycles). These data come from in vitro studies on cell lines and in vivo studies on transgenic animals: future investigations should be focused on physiologically relevant models to gain a better understanding of this topic.

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Retrotransposition of Long Interspersed Element 1 Induced by Methamphetamine or Cocaine

Cited by 28 publications

References 60 publications

Reading LINEs within the cocaine addicted brain

Reading LINEs within the cocaine addicted brain

Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation

Long INterspersed element‐1 mobility as a sensor of environmental stresses

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