MicroRNAs as Neuroregulators

  • Ketan S. Patil
  • Simon G. MøllerEmail author
Reference work entry


Neurodegeneration affects millions of individuals worldwide, and our knowledge of its disease pathogenesis is constantly changing with new research. The lack of a complete understanding of its disease pathogenesis makes the development of therapy difficult, but the discovery that microRNAs are intimately linked to neurodegeneration has unraveled new avenues in the field. Numerous microRNAs have been shown to be deregulated in neurodegeneration and can further regulate the expression of genes involved in neurodegeneration. There are also an increasing number of studies showing the effect of diet and nutrition on microRNA expression. In addition, interactions between microRNA- and epigenetic-mediated gene regulatory circuits have been reported, promising to increase our understanding of microRNAs within a bigger picture. In this chapter we review the role of microRNAs in neurodegeneration and how various endogenous and exogenous factors, including diet and nutrition, may influence the overall context.


MicroRNAs Neurodegeneration Nutrition Disease Regulation 

List of Abbreviations


Alzheimer’s disease


Amyotrophic lateral sclerosis


Amyloid precursor protein

Amyloid beta


Beta-secretase 1


B-cell lymphoma 2 protein


Corticobasal degeneration


CAMP-responsive element-binding protein


Cerebrospinal fluid


Dementia with Lewy bodies


DNA (cytosine-5)-methyltransferase 3A


Early growth response protein 1


Effect of epigenetic modifications on miRNAs


Enhancer RNA


Histone H3 protein subunit




Histone deacetylase 5




Locked nucleic acid


Leucine-rich repeat kinase 2


Effect of miRNAs on epigenetic modifications




Multiple system atrophy


Non-coding RNA


Neurofilament heavy subunit




Processing bodies


Parkinson’s disease


Programmed cell death protein 4


Primary miRNA


Progressive supranuclear palsy


Polypyrimidine tract-binding protein-1 (PTBP1)


Spinocerebellar ataxia






Serine palmitoyl transferase 1


Transcription factors


Trinucleotide repeat disorders


Unified Parkinson’s disease rating scale


  1. Abdullah R, Basak I, Patil KS et al (2015) Parkinson's disease and age: the obvious but largely unexplored link. Exp Gerontol 68:33–38CrossRefPubMedGoogle Scholar
  2. Ambros V, Bartel B, Bartel DP et al (2003) A uniform system for microRNA annotation. RNA 9:277–279CrossRefPubMedPubMedCentralGoogle Scholar
  3. Babak T, Zhang W, Morris Q et al (2004) Probing microRNAs with microarrays: tissue specificity and functional inference. RNA 10:1813–1819CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bargaje R, Hariharan M, Scaria V et al (2010) Consensus miRNA expression profiles derived from interplatform normalization of microarray data. RNA 16:16–25CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297CrossRefPubMedPubMedCentralGoogle Scholar
  6. Basak I, Patil K, Alves G et al (2015) microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases. Cell Mol Life Sci:1–17Google Scholar
  7. Behm-Ansmant I, Rehwinkel J, Doerks T et al (2006) mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes. Genes Dev 20:1885–1898CrossRefPubMedPubMedCentralGoogle Scholar
  8. Berezikov E, Thuemmler F, van Laake LW et al (2006) Diversity of microRNAs in human and chimpanzee brain. Nat Genet 38:1375–1377CrossRefPubMedGoogle Scholar
  9. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10(Suppl):S2–S9CrossRefPubMedGoogle Scholar
  10. Boutla A, Delidakis C, Tabler M (2003) Developmental defects by antisense-mediated inactivation of micro-RNAs 2 and 13 in drosophila and the identification of putative target genes. Nucleic Acids Res 31:4973–4980CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chahine LM, Stern MB (2011) Diagnostic markers for Parkinson's disease. Curr Opin Neurol 24:309–317CrossRefPubMedGoogle Scholar
  12. Chen W, Qin C (2015) General hallmarks of microRNAs in brain evolution and development. RNA Biol 12:701–708CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chen JA, Wichterle H (2012) Apoptosis of limb innervating motor neurons and erosion of motor pool identity upon lineage specific dicer inactivation. Front Neurosci 6:69CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cimmino A, Calin GA, Fabbri M et al (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 102:13944–13949CrossRefPubMedPubMedCentralGoogle Scholar
  15. Conaco C, Otto S, Han JJ et al (2006) Reciprocal actions of REST and a microRNA promote neuronal identity. Proc Natl Acad Sci U S A 103:2422–2427CrossRefPubMedPubMedCentralGoogle Scholar
  16. Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110:483–495CrossRefPubMedGoogle Scholar
  17. Dai E, Yu X, Zhang Y et al (2014) EpimiR: a database of curated mutual regulation between miRNAs and epigenetic modifications. Database (Oxford) 2014:bau023CrossRefGoogle Scholar
  18. Dannemann M, Prufer K, Lizano E et al (2012) Transcription factors are targeted by differentially expressed miRNAs in primates. Genome Biol Evol. 4:552–564CrossRefPubMedPubMedCentralGoogle Scholar
  19. Dickson JR, Kruse C, Montagna DR et al (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem 127:739–749CrossRefPubMedGoogle Scholar
  20. Doxakis E (2010) Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem 285:12726–12734CrossRefPubMedPubMedCentralGoogle Scholar
  21. Etheridge A, Lee I, Hood L et al (2011) Extracellular microRNA: a new source of biomarkers. Mutat Res 717:85–90CrossRefPubMedPubMedCentralGoogle Scholar
  22. Fabbri M, Garzon R, Cimmino A et al (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104:15805–15810CrossRefPubMedPubMedCentralGoogle Scholar
  23. Garcia-Segura L, Perez-Andrade M, Miranda-Rios J (2013) The emerging role of MicroRNAs in the regulation of gene expression by nutrients. J Nutrigenet Nutrigenomics 6:16–31CrossRefPubMedGoogle Scholar
  24. Garzon R, Marcucci G, Croce CM (2010) Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9:775–789CrossRefPubMedPubMedCentralGoogle Scholar
  25. Geekiyanage H, Jicha GA, Nelson PT et al (2012) Blood serum miRNA: non-invasive biomarkers for Alzheimer's disease. Exp Neurol 235:491–496CrossRefPubMedGoogle Scholar
  26. Gehrke S, Imai Y, Sokol N et al (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466:637–641CrossRefPubMedPubMedCentralGoogle Scholar
  27. Giraldez AJ, Cinalli RM, Glasner ME et al (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science (New York, NY) 308:833–838CrossRefGoogle Scholar
  28. Goodall EF, Heath PR, Bandmann O et al (2013) Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front Cell Neurosci 7:178CrossRefPubMedPubMedCentralGoogle Scholar
  29. Han J, Lee Y, Yeom KH et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027CrossRefPubMedPubMedCentralGoogle Scholar
  30. Haramati S, Chapnik E, Sztainberg Y et al (2010) miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 107:13111–13116CrossRefPubMedPubMedCentralGoogle Scholar
  31. Hashimoto Y, Akiyama Y, Yuasa Y (2013) Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer. PLoS One 8:e62589CrossRefPubMedPubMedCentralGoogle Scholar
  32. Hebert SS, Horre K, Nicolai L et al (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 105:6415–6420CrossRefPubMedPubMedCentralGoogle Scholar
  33. Henke JI, Goergen D, Zheng J et al (2008) microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J 27:3300–3310CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hu HY, Guo S, Xi J et al (2011) MicroRNA expression and regulation in human, chimpanzee, and macaque brains. PLoS Genet 7:e1002327CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hu HY, He L, Fominykh K et al (2012) Evolution of the human-specific microRNA miR-941. Nat Commun 3:1145CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hutvagner G, Simard MJ, Mello CC et al (2004) Sequence-specific inhibition of small RNA function. PLoS Biol 2:E98CrossRefPubMedPubMedCentralGoogle Scholar
  37. Inukai S, de Lencastre A, Turner M et al (2012) Novel microRNAs differentially expressed during aging in the mouse brain. PLoS One 7:e40028CrossRefPubMedPubMedCentralGoogle Scholar
  38. Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosur Ps 79:368–376CrossRefGoogle Scholar
  39. Khalaj M, Tavakkoli M, Stranahan AW et al (2014) Pathogenic microRNA's in myeloid malignancies. Front Genet 5:361CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kim VN, Han J, Siomi MC (2009) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139CrossRefPubMedGoogle Scholar
  41. Kim J, Inoue K, Ishii J et al (2007b) A MicroRNA feedback circuit in midbrain dopamine neurons. Science (New York, NY) 317:1220–1224CrossRefGoogle Scholar
  42. Kim D, Nguyen MD, Dobbin MM et al (2007a) SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J 26:3169–3179CrossRefPubMedPubMedCentralGoogle Scholar
  43. Korla K, Arrigo P, Mitra CK (2013) Promoters, toll like receptors and microRNAs: a strange association. Indian J Biochem Biophys 50:169–176PubMedGoogle Scholar
  44. Kosaka N, Izumi H, Sekine K et al (2010) microRNA as a new immune-regulatory agent in breast milk. Silence 1:7CrossRefPubMedPubMedCentralGoogle Scholar
  45. Koval ED, Shaner C, Zhang P et al (2013) Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet 22:4127–4135CrossRefPubMedPubMedCentralGoogle Scholar
  46. Krichevsky AM, Sonntag KC, Isacson O et al (2006) Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 24:857–864CrossRefPubMedGoogle Scholar
  47. Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610CrossRefPubMedGoogle Scholar
  48. Landgraf P, Rusu M, Sheridan R et al (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lee Y, Ahn C, Han J et al (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425:415–419CrossRefPubMedGoogle Scholar
  50. Lee ST, Chu K, Im WS et al (2011) Altered microRNA regulation in Huntington's disease models. Exp Neurol 227:172–179CrossRefPubMedGoogle Scholar
  51. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefPubMedGoogle Scholar
  52. Li H, Xie H, Liu W et al (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677CrossRefPubMedPubMedCentralGoogle Scholar
  53. Lim LP, Lau NC, Garrett-Engele P et al (2005) Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433:769–773CrossRefPubMedGoogle Scholar
  54. Ludwig N, Leidinger P, Becker K et al (2016) Distribution of miRNA expression across human tissues. Nucleic Acids Res 44:3865–3877CrossRefPubMedPubMedCentralGoogle Scholar
  55. MacRae IJ, Ma E, Zhou M et al (2008) Vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A 105:512–517CrossRefPubMedPubMedCentralGoogle Scholar
  56. Makeyev EV, Zhang J, Carrasco MA et al (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27:435–448CrossRefPubMedPubMedCentralGoogle Scholar
  57. Margis R, Margis R, Rieder CR (2011) Identification of blood microRNAs associated to Parkinson’s disease. J Biotechnol 152:96–101CrossRefPubMedGoogle Scholar
  58. Marti E, Pantano L, Banez-Coronel M et al (2010) A myriad of miRNA variants in control and Huntington's disease brain regions detected by massively parallel sequencing. Nucleic Acids Res 38:7219–7235CrossRefPubMedPubMedCentralGoogle Scholar
  59. Miller TM, Pestronk A, David W et al (2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 12:435–442CrossRefPubMedPubMedCentralGoogle Scholar
  60. Minones-Moyano E, Porta S, Escaramis G et al (2011) MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet 20:3067–3078CrossRefPubMedGoogle Scholar
  61. Miyoshi K, Miyoshi T, Siomi H (2010) Many ways to generate microRNA-like small RNAs: non-canonical pathways for microRNA production. Mol Gen Genomics 284:95–103CrossRefGoogle Scholar
  62. Ortega FJ, Mercader JM, Catalan V et al (2013) Targeting the circulating microRNA signature of obesity. Clin Chem 59:781–792CrossRefPubMedGoogle Scholar
  63. Persengiev S, Kondova I, Otting N et al (2011) Genome-wide analysis of miRNA expression reveals a potential role for miR-144 in brain aging and spinocerebellar ataxia pathogenesis. Neurobiol Aging 32(2316):e2317–e2327Google Scholar
  64. Petersen CP, Bordeleau ME, Pelletier J et al (2006) Short RNAs repress translation after initiation in mammalian cells. Mol Cell 21:533–542CrossRefPubMedGoogle Scholar
  65. Pillai RS, Artus CG, Filipowicz W (2004) Tethering of human ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA 10:1518–1525CrossRefPubMedPubMedCentralGoogle Scholar
  66. Pogue AI, Cui JG, Li YY et al (2010) Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neurosci Lett 476:18–22CrossRefPubMedGoogle Scholar
  67. Poy MN, Eliasson L, Krutzfeldt J et al (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230CrossRefPubMedPubMedCentralGoogle Scholar
  68. Poy MN, Hausser J, Trajkovski M et al (2009) miR-375 maintains normal pancreatic alpha- and beta-cell mass. Proc Natl Acad Sci U S A 106:5813–5818CrossRefPubMedPubMedCentralGoogle Scholar
  69. Prats-Puig A, Ortega FJ, Mercader JM et al (2013) Changes in circulating microRNAs are associated with childhood obesity. J Clin Endocrinol Metab 98:E1655–E1660CrossRefPubMedGoogle Scholar
  70. Ross SA, Davis CD (2014) The emerging role of microRNAs and nutrition in modulating health and disease. Annu Rev Nutr 34:305–336CrossRefPubMedGoogle Scholar
  71. Ruby JG, Jan CH, Bartel DP (2007) Intronic microRNA precursors that bypass Drosha processing. Nature 448:83–86CrossRefPubMedPubMedCentralGoogle Scholar
  72. Ryan BM, Robles AI, Harris CC (2010) Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389–402CrossRefPubMedPubMedCentralGoogle Scholar
  73. Saba R, Goodman CD, Huzarewich RL et al (2008) A miRNA signature of prion induced neurodegeneration. PLoS One 3:e3652CrossRefPubMedPubMedCentralGoogle Scholar
  74. Schratt GM, Tuebing F, Nigh EA et al (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289CrossRefPubMedGoogle Scholar
  75. Sempere LF, Freemantle S, Pitha-Rowe I et al (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5:R13CrossRefPubMedPubMedCentralGoogle Scholar
  76. Serafin A, Foco L, Zanigni S et al (2015) Overexpression of blood microRNAs 103a, 30b, and 29a in L-dopa-treated patients with PD. Neurology 84:645–653CrossRefPubMedGoogle Scholar
  77. Shah MS, Davidson LA, Chapkin RS (2012) Mechanistic insights into the role of microRNAs in cancer: influence of nutrient crosstalk. Front Genet 3:305CrossRefPubMedPubMedCentralGoogle Scholar
  78. Shi Y, Zhao X, Hsieh J et al (2010) MicroRNA regulation of neural stem cells and neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 30:14931–14936CrossRefGoogle Scholar
  79. Simone NL, Soule BP, Ly D et al (2009) Ionizing radiation-induced oxidative stress alters miRNA expression. PLoS One 4:e6377CrossRefPubMedPubMedCentralGoogle Scholar
  80. Siomi H, Siomi MC (2010) Posttranscriptional regulation of microRNA biogenesis in animals. Mol Cell 38:323–332CrossRefPubMedGoogle Scholar
  81. Smit-McBride Z, Forward KI, Nguyen AT et al (2014) Age-dependent increase in miRNA-34a expression in the posterior pole of the mouse eye. Mol Vis 20:1569–1578PubMedPubMedCentralGoogle Scholar
  82. Swierniak M, Wojcicka A, Czetwertynska M et al (2013) In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma. J Clin Endocrinol Metab 98:E1401–E1409CrossRefPubMedPubMedCentralGoogle Scholar
  83. Tarallo S, Pardini B, Mancuso G et al (2014) MicroRNA expression in relation to different dietary habits: a comparison in stool and plasma samples. Mutagenesis 29:385–391CrossRefPubMedGoogle Scholar
  84. Thum T, Catalucci D, Bauersachs J (2008) MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 79:562–570CrossRefPubMedGoogle Scholar
  85. Turchinovich A, Weiz L, Burwinkel B (2012) Extracellular miRNAs: the mystery of their origin and function. Trends Biochem Sci 37:460–465CrossRefPubMedGoogle Scholar
  86. Tzur G, Israel A, Levy A et al (2009) Comprehensive gene and microRNA expression profiling reveals a role for microRNAs in human liver development. PLoS One 4:e7511CrossRefPubMedPubMedCentralGoogle Scholar
  87. Valencia-Sanchez MA, Liu J, Hannon GJ et al (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20:515–524CrossRefPubMedGoogle Scholar
  88. Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science (New York, NY) 318:1931–1934CrossRefGoogle Scholar
  89. Vester B, Wengel J (2004) LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry 43:13233–13241CrossRefPubMedGoogle Scholar
  90. Wahid F, Shehzad A, Khan T et al (2010) MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta 1803:1231–1243CrossRefPubMedGoogle Scholar
  91. Wang Z (2009) miRNA interference technologies. In MicroRNA Interference Technologies, pp 59–73. Berlin, Heidelberg: SpringerGoogle Scholar
  92. Wang WX, Huang Q, Hu Y et al (2011) Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 121:193–205CrossRefPubMedGoogle Scholar
  93. Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75:855–862CrossRefPubMedGoogle Scholar
  94. Wu L, Fan J, Belasco JG (2006) MicroRNAs direct rapid deadenylation of mRNA. Proc Natl Acad Sci U S A 103:4034–4039CrossRefPubMedPubMedCentralGoogle Scholar
  95. Xiao M, Li J, Li W et al (2016) MicroRNAs activate Gene transcription epigenetically as an enhancer trigger. RNA Biol:0Google Scholar
  96. Yang D, Li T, Wang Y et al (2012) miR-132 regulates the differentiation of dopamine neurons by directly targeting Nurr1 expression. J Cell Sci 125:1673–1682CrossRefPubMedGoogle Scholar
  97. Zhang Z, Qin YW, Brewer G et al (2012) MicroRNA degradation and turnover: regulating the regulators. Wiley Interdiscip Rev RNA 3:593–600CrossRefPubMedPubMedCentralGoogle Scholar
  98. Zhao H, Guan J, Lee HM et al (2010) Up-regulated pancreatic tissue microRNA-375 associates with human type 2 diabetes through beta-cell deficit and islet amyloid deposition. Pancreas 39:843–846CrossRefPubMedGoogle Scholar
  99. Zhou R, Yuan P, Wang Y et al (2009) Evidence for selective microRNAs and their effectors as common long-term targets for the actions of mood stabilizers. Neuropsychopharmacology 34:1395–1405CrossRefPubMedGoogle Scholar
  100. Zisoulis DG, Kai ZS, Chang RK et al (2012) Autoregulation of microRNA biogenesis by let-7 and Argonaute. Nature 486:541–544CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Biological SciencesSt. John’s UniversityNew YorkUSA
  2. 2.Norwegian Center for Movement DisordersStavanger University HospitalStavangerNorway

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