MicroRNA dysregulation in schizophrenia

Schizophrenia is a complex neuropsychiatric disorder that involves disturbances in neural circuitry and synaptic function. The exquisite network architecture and capacity for discreet post-synaptic remodeling of neurons requires coordination by an elaborate intracellular network of molecular signal transduction systems. The redundancy of these networks means that many combinations of gene variants have the potential to cause system dysfunction that manifest as related neurobehavioural syndromes. Recent investigation has revealed that posttranscriptional gene regulation and associated small non-coding microRNA (miRNA), are likely to be important factors shaping the topography of these networks. miRNA display complex temporospatial expression patterns in the mammalian brain and have the potential to regulate thousands of target genes by functioning as the specificity factor for intracellular gene-silencing machinery. They are emerging as key regulators of many neurodevelopmental and neurological processes as their dysregulation could lead to pervasive changes in the network structure during development and in the mature brain that are highly significant in the pathophysiology of schizophrenia. This review looks at mounting evidence that mature miRNA levels are altered in both the cerebral cortex and peripheral blood mononuclear cells (PBMCs) in schizophrenia. It also examines compelling evidence that the underlying miRNA biogenesis machinery and miRNA genes themselves are subject to disease-associated genetic mutation and epigenetic influence. Significantly, these changes in miRNA expression and associated machinery may represent new targets for pharmaceutical development, and the identification of miRNA signatures in PBMCs suggest that miRNA biomarkers of schizophrenia may also provide the basis for new clinical diagnostics. These developments have tremendous potential and highlight the significance of this avenue of research.

[1]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[2]  Nikolaos Mellios,et al.  A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. , 2008, Human molecular genetics.

[3]  A. Roses,et al.  Identification of miRNA Changes in Alzheimer's Disease Brain and CSF Yields Putative Biomarkers and Insights into Disease Pathways , 2008 .

[4]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[5]  M. Cairns,et al.  Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells , 2011, Molecular Psychiatry.

[6]  Hyman M. Schipper,et al.  MicroRNA Expression in Alzheimer Blood Mononuclear Cells , 2007, Gene regulation and systems biology.

[7]  P. Falkai,et al.  Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. , 2010, Archives of general psychiatry.

[8]  Joseph A. Gogos,et al.  Strong association of de novo copy number mutations with sporadic schizophrenia , 2008, Nature Genetics.

[9]  J. Rubenstein,et al.  Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer , 2009, Molecular Psychiatry.

[10]  Anders D. Børglum,et al.  Genome-wide association study identifies five new schizophrenia loci , 2011, Nature Genetics.

[11]  R. Huganir,et al.  Bipolar I Disorder and Schizophrenia : A 440 – Single-Nucleotide Polymorphism Screen of 64 Candidate Genes among Ashkenazi Jewish , 2007 .

[12]  G. Kirov,et al.  De Novo Rates and Selection of Schizophrenia-Associated Copy Number Variants , 2011, Biological Psychiatry.

[13]  G. Hannon,et al.  A MicroRNA Feedback Circuit in Midbrain Dopamine Neurons , 2007, Science.

[14]  Byoung-Tak Zhang,et al.  Molecular Basis for the Recognition of Primary microRNAs by the Drosha-DGCR8 Complex , 2006, Cell.

[15]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[16]  Guang Chen,et al.  Evidence for Selective microRNAs and Their Effectors as Common Long-Term Targets for the Actions of Mood Stabilizers , 2009, Neuropsychopharmacology.

[17]  Karl J. Friston.  The disconnection hypothesis , 1998, Schizophrenia Research.

[18]  Mathew B. Cox,et al.  MicroRNAs miR-17 and miR-20a Inhibit T Cell Activation Genes and Are Under-Expressed in MS Whole Blood , 2010, PloS one.

[19]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[20]  H. Zoghbi,et al.  Neurobiology of disease , 2000, Current Opinion in Neurobiology.

[21]  Molly Megraw,et al.  miRGen: a database for the study of animal microRNA genomic organization and function , 2006, Nucleic Acids Res..

[22]  S. Hébert,et al.  Alterations of the microRNA network cause neurodegenerative disease , 2009, Trends in Neurosciences.

[23]  P. Jin,et al.  RNA and microRNAs in fragile X mental retardation , 2004, Nature Cell Biology.

[24]  Bin Xu,et al.  Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex , 2011, Proceedings of the National Academy of Sciences.

[25]  P. Jin,et al.  Cross talk between microRNA and epigenetic regulation in adult neurogenesis , 2010, The Journal of cell biology.

[26]  R. Shprintzen,et al.  Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Cairns,et al.  Dysregulation of miRNA 181b in the temporal cortex in schizophrenia. , 2008, Human molecular genetics.

[28]  C. Perou,et al.  A custom microarray platform for analysis of microRNA gene expression , 2004, Nature Methods.

[29]  M. Cairns,et al.  Schizophrenia is associated with an increase in cortical microRNA biogenesis , 2009, Molecular Psychiatry.

[30]  John J Rossi,et al.  SNPs in human miRNA genes affect biogenesis and function. , 2009, RNA.

[31]  Joel S Parker,et al.  Extensive post-transcriptional regulation of microRNAs and its implications for cancer. , 2006, Genes & development.

[32]  Jin Yan,et al.  Evidence for X-Chromosomal Schizophrenia Associated with microRNA Alterations , 2009, PloS one.

[33]  Gene W. Yeo,et al.  Noncoding RNAs in the mammalian central nervous system. , 2006, Annual review of neuroscience.

[34]  B. Cullen,et al.  Efficient Processing of Primary microRNA Hairpins by Drosha Requires Flanking Nonstructured RNA Sequences* , 2005, Journal of Biological Chemistry.

[35]  Murray J. Cairns,et al.  Upregulation of Dicer and MicroRNA Expression in the Dorsolateral Prefrontal Cortex Brodmann Area 46 in Schizophrenia , 2011, Biological Psychiatry.

[36]  P. Nelson,et al.  MiR-107 is reduced in Alzheimer's disease brain neocortex: validation study. , 2010, Journal of Alzheimer's disease : JAD.

[37]  M. Hentze,et al.  Molecular mechanisms of translational control , 2004, Nature Reviews Molecular Cell Biology.

[38]  Lin He,et al.  A Case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population , 2007, Schizophrenia Research.

[39]  B. Cullen,et al.  Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha , 2005, The EMBO journal.

[40]  Anton J. Enright,et al.  RNA editing of human microRNAs , 2006, Genome Biology.

[41]  W. Filipowicz,et al.  Inhibition of Translational Initiation by Let-7 MicroRNA in Human Cells , 2005, Science.

[42]  T. Kalbfleisch,et al.  A MicroRNA gene is hosted in an intron of a schizophrenia-susceptibility gene , 2009, Schizophrenia Research.

[43]  Yukio Kawahara,et al.  RNA editing of the microRNA‐151 precursor blocks cleavage by the Dicer–TRBP complex , 2007, EMBO reports.

[44]  Kerang Zhang,et al.  MicroRNAs and target site screening reveals a pre-microRNA-30e variant associated with schizophrenia , 2010, Schizophrenia Research.

[45]  Michael T. McManus,et al.  Dicer loss in striatal neurons produces behavioral and neuroanatomical phenotypes in the absence of neurodegeneration , 2008, Proceedings of the National Academy of Sciences.

[46]  Paul Pavlidis,et al.  Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model , 2008, Nature Genetics.

[47]  Claes Wahlestedt,et al.  MicroRNA-219 modulates NMDA receptor-mediated neurobehavioral dysfunction , 2009, Proceedings of the National Academy of Sciences.

[48]  A. Hatzigeorgiou,et al.  A guide through present computational approaches for the identification of mammalian microRNA targets , 2006, Nature Methods.

[49]  R. Huganir,et al.  Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. , 2005, American journal of human genetics.

[50]  Guiliang Tang,et al.  miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. , 2010, The American journal of pathology.

[51]  Vladimir I. Vladimirov,et al.  MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders , 2010, Schizophrenia Research.

[52]  K. Lindblad-Toh,et al.  Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals , 2005, Nature.

[53]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[54]  S. Akbarian.  MOLECULAR DETERMINANTS OF DYSREGULATED GABAERGIC GENE EXPRESSION IN THE PREFRONTAL CORTEX OF SUBJECTS WITH SCHIZOPHRENIA , 2010, Schizophrenia Research.

[55]  A. Hatzigeorgiou,et al.  A combined computational-experimental approach predicts human microRNA targets. , 2004, Genes & development.

[56]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[57]  P. Jin,et al.  MicroRNA miR‐137 Regulates Neuronal Maturation by Targeting Ubiquitin Ligase Mind Bomb‐1 , 2010, Stem cells.

[58]  Ole A. Andreassen,et al.  Brain Expressed microRNAs Implicated in Schizophrenia Etiology , 2007, PloS one.

[59]  H. Hwu,et al.  MicroRNA Expression Aberration as Potential Peripheral Blood Biomarkers for Schizophrenia , 2011, PloS one.

[60]  Rosanna Weksberg,et al.  The schizophrenia phenotype in 22q11 deletion syndrome. , 2003, The American journal of psychiatry.

[61]  Robert Blelloch,et al.  Monoallelic deletion of the microRNA biogenesis gene Dgcr8 produces deficits in the development of excitatory synaptic transmission in the prefrontal cortex , 2011, Neural Development.

[62]  P. Seeburg,et al.  Modulation of microRNA processing and expression through RNA editing by ADAR deaminases , 2006, Nature Structural &Molecular Biology.

[63]  Joel S Parker,et al.  microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder , 2007, Genome Biology.

[64]  Richard David-Rus,et al.  Altered MicroRNA Expression Profiles in Postmortem Brain Samples from Individuals with Schizophrenia and Bipolar Disorder , 2011, Biological Psychiatry.

[65]  Murat Gunel,et al.  Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome , 2005, Science.

[66]  Lawrence S. Hon,et al.  The roles of binding site arrangement and combinatorial targeting in microRNA repression of gene expression , 2007, Genome Biology.

[67]  Nikolaos Mellios,et al.  Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia. , 2012, Schizophrenia bulletin.

[68]  M. Owen,et al.  High rates of schizophrenia in adults with velo-cardio-facial syndrome (VCFS) , 1999, Schizophrenia Research.