Neuropsychiatric diseases, such as schizophrenia, bipolar disorder (BD), major depressive disorder (MDD) and autism spectrum disorder (ASD), are a huge burden on society, impairing the health of those affected, as well as their ability to learn and work. Biomarkers that reflect the dysregulations linked to neuropsychiatric diseases may potentially assist the diagnosis of these disorders. Most of these biomarkers are found in the brain tissue, which is not easily accessible. This is the challenge for the search of novel biomarkers that are present in various body fluids, including serum or plasma. As a group of important endogenous small noncoding RNAs that regulate gene expression at post-transcriptional level, microRNAs (miRNAs) play a crucial role in many physiological and pathological processes. Previously, researchers discovered that miRNAs contribute to the neurodevelopment and maturation, including neurite outgrowth, dendritogenesis and dendritic spine formation. These developments underline the significance of miRNAs as potential biomarkers for diagnosing and prognosing central nervous system diseases. Accumulated evidence indicates that there are considerable differences between the cell-free miRNA expression profiles of healthy subjects and those of patients. Therefore, circulating miRNAs are likely to become a new class of noninvasive, sensitive biomarkers. Despite the fact that little is known about the origin and functions of circulating miRNAs, their essential roles in the clinical diagnosis and prognosis of neuropsychiatric diseases make them attractive biomarkers. In this review we cover the increasing amounts of dataset that have accumulated in the last years on the use of circulating miRNAs and their values as potential biomarkers in most areas of neuropsychiatric diseases.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Giacoma De Tullio Vincenza De Fazio Nicola Sgherza et al. Challenges and opportunities of MicroRNAs in lymphomas. Molecules 2014;19:14723-781.
2. Friedman RC Farh KK Burge CB et al. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 2009;19:92-105.
3. Olive V Jiang I He L. Mir-17-92 a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol 2010;42:1348-54.
4. Ma L Teruya-Feldstein J Weinberg RA. Tumour invasion and metastasis initiated by microRNA 10b in breast cancer. Nature 2007;449:682-8.
5. Peter ME. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle 2009;8:843-52.
6. Visone R Pallante P Vecchione A et al. Specifi c microRNAs are downregulated in human thyroid anaplastic carcinomas. Oncogene 2007;26:7590-5.
7. Nam EJ Yoon H Kim SW et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008;14:2690-5.
8. Le MT Teh C Shyh-Chang N et al. MicroRNA 125b is a novel negative regulator of p53. Genes Dev 2009;23:862-76.
9. Ozen M Creighton CJ Ozdemir M et al. Widespread deregulation of microRNA expression in human prostate cancer. Oncogene 2008;27:1788-93.
10. Rosenfeld N Aharonov R Meiri E et al. MicroRNAs accurately identify cancer tissue origin. Nat Biotechnol 2008;26:462-9.
11. Weber JA Baxter DH Zhang S et al. The microRNA spectrum in 12 body fluids. Clin Chem 2010;56:1733-41.
12. Kosaka N Izumi H Sekine K et al. MicroRNA as a new immune-regulatory agent in breast milk. Silence 2010;1:7.
13. Cai X Hagedorn CH Cullen BR. Human microRNAs are processed from capped polyadenylated transcripts that can also function as mRNAs. RNA 2004;10:1957-66.
14. Krol J Loedige I Filipowicz W. The widespread regulation of microRNA biogenesis function and decay. Nat Rev Genet 2010;11:597-610.
15. Winter J Jung S Keller S et al. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol 2009;11:228-34.
16. Zen K Zhang CY. Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers. Med Res Rev 2012;32:326-48.
17. Tsui NB Ng EK Lo YM Stability of endogenous and added RNA in blood specimens serum and plasma. Clin Chem 2002;48:1647-53.
18. Chen X Ba Y Ma L et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 2008;18:997-1006.
19. Valadi H Ekström K Bossios A et al. Exosomemediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654-59.
20. Smalheiser NR. Exosomal transfer of proteins and RNAs at synapses in the nervous system. Biol Direct 2007;2:35-49.
21. Camussi G Deregibus MC Bruno S et al. Exosomes/ microvesicles as a mechanism of cell-to-cell communication. Kidney Int 2010;78:838-48.
22. Ratajczak J Wysoczynski M Hayek F et al. Membrane- derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 2006;20:1487-95.
23. Pegtel DM Cosmopoulos K Thorley-Lawson DA et al. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA 2010;107:6328-33.
24. Pigati L Yaddanapudi SC Iyengar R et al. Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One 2010;5:e13515.
25. Ratajczak J Miekus K Kucia M et al. Embryonic stem cell derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 2007;20:847-56.
26. Hunter MP Ismail N Zhang X et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 2008;3:e3694.
27. Yuan A Farber EL Rapoport AL et al. Transfer of microRNAs by embryonic stem cell microvesicles. PLoS One 2009;4:e4722.
28. Mack M Kleinschmidt A Bruhl H et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodefi ciency virus 1 infection. Nat Med 2000;6:769-75.
29. Mause SF Ritzel E Liehn EA et al. Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury. Circulation 2010;122:495-506.
30. Prokopi M Pula G Mayr U et al. Proteomic analysis reveals presence of platelet microparticles in endothelial progenitor cell cultures. Blood 2009;114:723-32.
31. Zhang Y Liu D Chen X et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 2010;39:133-44.
32. Beyer C Pisetsky DS. The role of microparticles in the pathogenesis of rheumatic diseases. Nat Rev Rheumatol 2010;6:21-9.
33. Hristov M Erl W Linder S et al. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood 2004;104:2761-6.
34. Zampetaki A Willeit P Drozdov I et al. Profi ling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc Res 2012;93:555-62.
35. Vickers KC Palmisano BT Shoucri BM et al. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 2011;13:423-33.
36. Arroyo JD Chevillet JR Kroh EM et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA 2011;108:5003-8
37. Wang K Zhang S Weber J et al. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res 2010;38:7248-59.
38. Cocucci E Racchetti G Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol 2009;19:43-51.
39. Iguchi H Kosaka N Ochiya T. Secretory microRNAs as a versatile communication tool. Commun Integr Biol 2010;3:478-81.
40. Kim YK Yeo J Kim B et al. Short structured RNAs with low GC content are selectively lost during extraction from a small number of cells. Mol Cell 2012;46:893-5.
41. Metzker ML. Sequencing technologies - the next generation. Nat Rev Genet 2010;11:31-46.
42. Shen J Stass SA Jiang F. MicroRNAs as potential biomarkers in human solid tumors. Cancer Lett 2013;329:125-36.
43. Ach RA Wang H Curry B. Measuring microRNAs: comparisons of microarray and quantitative PCR measurements and of different total RNA prep methods. BMC Biotechnol 2008;8:69.
44. Willenbrock H Salomon J Søkilde R et al. Quantitative miRNA expression analysis: comparing microarrays with next generation sequencing. RNA 2009;15:2028.
45. Sato F Tsuchiya S Terasawa K et al. Intra-platform repeatability and inter-platform comparability of microRNA microarray technology. PLoS One 2009;4:e5540.
46. Git A Dvinge H Salmon-Divon M et al. Systematic comparison of microarray profi ling real-time PCR and next-generation sequencing technologies for measuring differential microRNA expression. RNA 2010;16:991-1006.
47. Sah S McCall MN Eveleigh D et al. Performance evaluation of commercial miRNA expression array platforms. BMC Res Notes 2010;3:80.
48. Pradervand S Weber J Lemoine F et al. Concordance among digital gene expression microarrays and qPCR when measuring differential expression of microRNAs. Biotechniques 2010;48:219-222.
49. Yauk CL Rowan-Carroll A Stead JD et al. Crossplatform analysis of global microRNA expression technologies. BMC Genomics 2010;11:330.
50. Wang B Howel P Bruheim S et al. Systematic evaluation of three microRNA profi ling platforms: microarray beads array and quantitative real-time PCR array. PLoS One 2011;6:e17167.
51. Kolbert CP Feddersen RM Rakhshan F et al. Multi-platform analysis of microRNA expression measurements in RNA from fresh frozen and FFPE tissues. PLoS One 2013;8:e52517.
52. Del Vescovo V Meier T Inga A et al. A crossplatform comparison of affymetrix and Agilent microarrays reveals discordant miRNA expression in lung tumors of c-Raf transgenic mice. PLoS One 2013;8:e78870.
53. Chen C Ridzon DA Broomer AJ et al. Real-time quantification of microRNAs by stem-loop RT PCR. Nucleic Acids Res 2005;33:e179.
54. Fu HJ Zhu J Yang M et al. A novel method to monitor the expression of microRNAs. Mol Biotechnol 2006;32:197-204.
55. Ferdin J Kunej T Calin GA. Non-coding RNAs: identification of cancer-associated microRNAs by gene profiling. Technol Cancer Res Treat 2010;9:123-38.
56. Takamizawa J Konishi H Yanagisawa K et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 2004;64:3753-6.
57. Kulshreshtha R Ferracin M Wojcik SE et al. A microRNA signature of hypoxia. Mol Cell Biol 2007;27:1859-67.
58. Nadano D Sato TA. Caspase-3-dependent and -independent degradation of 28 S ribosomal RNA may be involved in the inhibition of protein synthesis during apoptosis initiated by death receptor engagement. J Biol Chem 2000;275:13967-73.
59. Chan MW Wei SH Wen P et al. Hypermethylation of 18S and 28S ribosomal DNAs predicts progression free survival in patients with ovarian cancer. Clin Cancer Res 2005;11:7376-83.
60. Patnaik SK Kannisto E Knudsen S et al. Evaluation of microRNA expression profiles that may predict recurrence of localized stage I non-small cell lung cancer after surgical resection. Cancer Res 2010;70:36-45.
61. Peltier HJ Latham GJ. Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. RNA 2008;14:844-52.
62. Gee HE Buffa FM Camps C et al. The smallnucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis. Br J Cancer 2011;104:1168-77.
63. Hindson CM Chevillet JR Briggs HA et al. Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat Methods 2013;10:1003-5.
64. Sepramaniam S Tan JR Tan KS et al. Circulating microRNAs as biomarkers of acute stroke. Int J Mol Sci 2014;15:1418-32.
65. Ma L Wei L Wu F et al. Advances with microRNAs in Parkinson’s disease research. Drug Des Devel Ther 2013;7:1103-13.
66. Kumar P Dezso Z MacKenzie C et al. Circulating miRNA biomarkers for Alzheimer’s disease. PLoS One 2013;8:e69807.
67. Shi W Du J Qi Y et al. Aberrant expression of serum miRNAs in schizophrenia. J Psychiatr Res 2012;46:198-204.
68. Heese K Akatsu H. Alzheimer’s disease: an interactive perspective. Curr Alzheimer Res 2006;3:109-21.
69. Geekiyanage H Jicha GA Nelson PT et al. Blood serum miRNA: non-invasive biomarkers for Alzheimer’s disease. Exp Neurol 2012;235:491-6.
70. Hebert SS Horre K Nicolai L et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/ betasecretase expression. Proc Natl Acad Sci USA 2008;105:6415-20.
71. Wang WX Huang Q Hu Y et al. Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 2011;121:193-205.
72. Geekiyanage H Chan C MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta novel targets in sporadic Alzheimer’s disease. J Neurosci 2011 31:14820-30.
73. Lin DH Yue P et al. MicroRNA 802 stimulates ROMK channels by suppressing caveolin-1. Journal of the American Society of Nephrology 2011;22:1087-98.
74. Maes OC Chertkow et al. MicroRNA: implications for Alzheimer disease and other human CNS disorders. Current Genomics 2009;10:154-68.
75. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971-983.
76. He L He X Lim LP et al. A microRNA component of the p53 tumour suppressor network. Nature 2007;447:1130-4.
77. Oertel-Knochel V Bittner RA Knochel C et al. Discovery and development of integrative biological markers for schizophrenia. Prog Neurobiol 2011;95:686-702.
78. van Os J Rutten BP Poulton R. Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull 2008;34:1066-82.
79. Perkins DO Jeffries CD Jarskog LF et al. microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol 2007;8:R27.
80. Shi W Du J Qi Y et al. Aberrant expression of serum miRNAs in schizophrenia. J Psychiatr Res 2012;46:198-204.
81. Beveridge NJ Cairns MJ. microRNA dysregulation in schizophrenia. Neurobiol Dis 2012;46:263-71.
82. Lett TA Chakavarty MM Felsky D et al. The genome wide supported microRNA 137 variant predicts phenotypic heterogeneity within schizophrenia. Mol Psychiatry 2013;18:443-50.
83. Popov N Stoyanova V Majirova N et al. Epigenetic aspects in schizophrenia etiology and pathogenesis. Folia Medica 2012;54:12-7.
84. Rong H Liu TB Yang KJ et al. MicroRNA-134 plasma levels before and after treatment for bipolar mania. J Psychiatr Res 2011;45:92-5.
85. Broadhead WE Blazer DG George LK et al. Depression disability days and days lost from work in a prospective epidemiologic survey. JAMA 1990;264:2524-8.
86. Pompili M Innamorati M Rihmer Z et al. Cyclothymic- depressive-anxious temperament pattern is related to suicide risk in 346 patients with major mood disorders. J Affect Disord 2012;136:405-11.
87. Innamorati M Pompili M Gonda X et al. Psychometric properties of the Gotland Scale for Depression in Italian psychiatric inpatients and its utility in the prediction of suicide risk. J Affect Disord 2011;132:99-103.
88. Ota KT Duman RS. Environmental and pharmacological modulations of cellular plasticity: role in the pathophysiology and treatment of depression. Neurobiol Dis 2013;57:28-37.
89. Belzeaux R Bergon A Jeanjean V et al. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode. Transl Psychiatry 2012;2:e185
90. Smalheiser NR Lugli G Rizavi HS et al. MicroRNA expression is downregulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One 2012;7:e33201.
91. Meek SE Lemery-Chalfant K Jahromi LB et al. A review of gene environment correlations and their implications for autism: a conceptual model. Psychol Rev 2013 120:497-521.
92. Delcuve GP Rastegar M Davie JR. Epigenetic control. J Cell Physiol 2009;219:243-250.
93. Mundalil Vasu M Anitha A Thanseem I et al. Serum microRNA profi les in children with autism. Mol Autism 2014;5:40.
94. Abu-Elneel K Liu T Gazzaniga FS et al. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics 2008;9:153-61.
95. Talebizadeh Z Butler MG Theodoro MF. Feasibility and relevance of examining lymphoblastoid cell lines to study role of microRNAs in autism. Autism Res 2008;1:240-50.
96. Sarachana T Zhou R Chen G et al. Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profi ling of lymphoblastoid cell lines. Genome Med 2010;2:23.
97. Ghahramani Seno MM Hu P Gwadry FG et al. Gene and miRNA expression profiles in autism spectrum disorders. Brain Res 2011;1380:85-97.
98. Vachev T Minkov I Stoyanova V et al. Down regulation of miRNA let-7b-3p and let-7d-3p in the peripheral blood of children with autism spectrum disorder. Int J Curr Microbiol App Sci 2013;2;384-8.
99. Huntzinger E Izaurralde E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011;12:99-110.
100. Fabian MR Sonenberg N Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 2010;79:351-79.
101. Suda S Iwata K Shimmura C et al. Decreased expression of axon-guidance receptors in the anterior cingulate cortex in autism. Mol Autism 2011;2:14.
102. Anitha A Nakamura K Thanseem I et al. Downregulation of the expression of mitochondrial electron transport complex genes in autism brains. Brain Pathol 2013;23:294-302.
103. Hu VW Nguyen A Kim KS et al. Gene expression profi ling of lymphoblasts from autistic and nonaffected sib pairs: altered pathways in neuronal development and steroid biosynthesis. PLoS One 2009;4:e5775.