Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder

Bavamian, Sabine; Mellios, Nikolaos; Lalonde, Jasmin; Fass, Daniel M.; Wang, Jennifer; Sheridan, Steven D.; Madison, Jon M.; Zhou, Fangjian; Rueckert, Erroll H.; Barker, Doug; Perlis, Roy H.; Sur, Mriganka; Haggarty, Stephen J.

doi:10.1038/mp.2014.176

Cited by 142 publications

(115 citation statements)

References 76 publications

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“…Dysregulation of miR-34a is increased in neural development and a genetic risk factor for bipolar disorder (BD) patients. δ-tocotrienol treatment of participants in the present study resulted in significant down-regulation of miR34a, suggesting that this supplement may have a beneficial effect in the treatment of BD patients [38]. Expression of miR-107, miR-122a, and miR-132 decreases during the early stage of Alzheimer's disease, and disease progression is accelerated through regulation of b-site amyloid precursor protein-cleaving enzyme-1.…”

Section: Discussionmentioning

confidence: 80%

Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

Qureshi¹,

Khan²,

Saleem³

et al. 2015

J Clin Exp Cardiolog

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Background: Although, α-tocopherol is the most bioavailable form of vitamin E, but several animal and clinical studies have demonstrated tocotrienol bioavailability to various tissues. There are few reports on bioavailability of tocotrienols in humans. Most studies were carried out with mixtures of tocotrienols + tocopherols rather than pure tocotrienols. Moreover, dietary α-tocopherol interferes with the bioavailability of tocotrienols, and prevents absorption and delivery to organs and tissues.Aim: Pharmacokinetics and bioavailability of annatto-based δ-tocotrienol, plasma levels of α-, β-, γ-, δ-tocotrienol and tocopherols were quantified. In addition, several cytokines and microRNAs were examined. Study design:An open-label, randomized study evaluated pharmacokinetics and bioavailability of δ-tocotrienol in 33 healthy fed subjects. All subjects (11/dose) were randomly assigned to doses of 125, 250, or 500 mg/d. Plasma samples collected at 0, 1, 2, 3, 4, 6, 8, 10 h intervals were estimated by HPLC for tocols (tocotrienols and tocopherols). Results:The present study describes the effects of δ-tocotrienol on pharmacokinetic parameters of all eight tocol isomers. Supplementation of 125, 250 and 500 mg/d doses resulted in dose-dependent increases of (a) area under concentration-time curve (AUC t0 -t10 , ng/ml) 2464, 5412, 14986; (b) maximum concentration (C max , ng/ml) 829, 1920, 3278 (P<0.001); (c) time to achieve maximum peak (T max ; h) 3, 3, 6; (d) elimination of half-life (t 1/2 h) 1.74, 1.39, 2.54; (e) time of clearance (Cl-T, h -1 ) 0.049, 0.045, 0.030; (f) volume of distribution (Vd/f, mg/h) 0.119, 0.114, 0.113; and (g) elimination rate constant (Ke; h -1 ) 0.412, 0.401, 0.265. Similar results were reported for the other tocols. Maximum plasma levels of δ-tocotrienol were observed at 3 h with doses of 125 and 250 mg/d, and 6 h with 500 mg/d. γ-tocotrienol, β-tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol β-tocopherol and α-tocopherol were appeared in the plasma after 2 h. Moreover, δ-tocotrienol treatment resulted in down-regulation of eight cytokines and upregulation of adiponectin, TGF-β1, and leptin. The expression of miR-34a (increased in bipolar disorder) was down-regulated, but expression of miR-107, miR-122a, and miR-132 (decreased in Alzheimer's disease) was upregulated by δ-tocotrienol treatment.Conclusion: This is the first study describing the effect of δ-tocotrienol on pharmacokinetics and bioavailability of all eight tocol isomers. When tocotrienols are supplemented in absence of tocopherols, δ-tocotrienol has better bioavailability, and δ-tocotrienol is converted stepwise to other tocotrienols/tocopherols. These results support that tocotrienol, particularly δ-tocotrienol, as a dietary supplement might be useful in the prevention of age-related and chronic ailments. Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects IntroductionSeveral studies have reported the antioxidant, anti-inflammatory, anticancer, hypocholesterolemic and neuroprotec...

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Section: Discussionmentioning

confidence: 80%

Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

Qureshi¹,

Khan²,

Saleem³

et al. 2015

J Clin Exp Cardiolog

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“…While miRNA expression has been examined across a multitude of psychiatric illnesses, encompassing several brain regions, cell types and blood (Bavamian et al, 2015, Fan et al, 2014, Kim, Reimers, 2010, Miller, Zeier, 2012, Moreau, Bruse, 2011, Sun et al, 2015, Walker et al, 2015), to our knowledge this is the first work to examine miRNAs dysregulated as a function of psychiatric illness in AnCg. Additionally, comparing prior work examining miRNA dysregulation in the DLPFC—another brain region of intense interest in the pathology of mental illness—of BP and MDD patients to our results in AnCg, we see little overlap in the specific miRNA species dysregulated as a function of anatomy (e.g.…”

Section: Discussionmentioning

confidence: 99%

The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression

Azevedo

Carter

Meng

et al. 2016

Journal of Psychiatric Research

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MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR-34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness.

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“…2 c ) was shown to affect the expression of hsa-miR-34a (miR-34a). An increased level of this miRNA was recently identified in the postmortem cerebellar tissue of BD patients (Bavamian et al 2015); increased miR-34a expression in human iPSC-derived neuronal progenitor cells impacts neuronal differentiation and morphology. The second most significant BD related finding was rs10114192 ( p = 0.016858, q = 0.0118006; Fig.…”

Section: Resultsmentioning

confidence: 98%

Expression quantitative trait loci (eQTLs) in microRNA genes are enriched for schizophrenia and bipolar disorder association signals

et al. 2015

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Background Schizophrenia (SZ) and bipolar disorder (BD) have substantial negative impact on the quality of human life. Both, microRNA (miRNA) expression profiling in SZ and BD postmortem brains [and genome-wide association studies (GWAS)] have implicated miRNAs in disease etiology. Here, we aim to determine whether significant GWAS signals observed in the Psychiatric Genetic Consortium (PGC) are enriched for miRNAs. Method A two-stage approach was used to determine whether association signals from PGC affect miRNAs: (i) statistical assessment of enrichment using a Simes test and sum of squares test (SST) and (ii) biological evidence that quantitative trait loci (eQTL) mapping to known miRNA genes affect their expression in an independent sample of 78 postmortem brains from the Stanley Medical Research Institute. Results A total of 2567 independent single nucleotide polymorphisms (SNPs) (R2 > 0.8) were mapped locally, within 1 Mb, to all known miRNAs (miRBase v. 21). We show robust enrichment for SZ- and BD-related SNPs with miRNAs using Simes (SZ: p ≤ 0.0023, BD: p ≤ 0.038), which remained significant after adjusting for background inflation in SZ (empirical p = 0.018) and approached significance in BD (empirical p = 0.07). At a false discovery rate of 10%, we identified a total of 32 eQTLs to influence miRNA expression; 11 of these overlapped with BD. Conclusions Our approach of integrating PGC findings with eQTL results can be used to generate specific hypotheses regarding the role of miRNAs in SZ and BD.

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Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder

Cited by 142 publications

References 76 publications

Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

Pharmacokinetics and Bioavailability of Annatto δ-tocotrienol in Healthy Fed Subjects

The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression

Expression quantitative trait loci (eQTLs) in microRNA genes are enriched for schizophrenia and bipolar disorder association signals

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