Molecular Neurobiology

, Volume 51, Issue 3, pp 1249–1262 | Cite as

Causes and Consequences of MicroRNA Dysregulation in Neurodegenerative Diseases

  • Lin Tan
  • Jin-Tai Yu
  • Lan Tan


Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), originate from a loss of neurons in the central nervous system (CNS) and are severely debilitating. The incidence of neurodegenerative diseases increases with age, and they are expected to become more common due to extended life expectancy. Because of no clear mechanisms, these diseases have become a major challenge in neurobiology. It is well recognized that these disorders become the culmination of many different genetic and environmental influences. Prior studies have shown that microRNAs (miRNAs) are pathologically altered during the inexorable course of some neurodegenerative diseases, suggesting that miRNAs may be the contributing factor in neurodegeneration. Here, we review what is known about the involvement of miRNAs in the pathogenesis of neurodegenerative diseases. The biogenesis of miRNAs and various functions of miRNAs that act as the chief regulators will be discussed. We focus in particular on dysregulation of miRNAs which leads to several neurodegenerative diseases from three aspects: miRNA-generating disorders, miRNA-targeting genes and epigenetic alterations. Furthermore, recent evidences have shown that circulating miRNA expression levels are changed in patients with neurodegenerative diseases. Circulating miRNA expression levels are reported in patients in order to evaluate their application as biomarkers of these diseases. A discussion is included with a potential diagnostic biomarker and the possible future direction in exploring the nexus between miRNAs and various neurodegenerative diseases.


Alzheimer’s disease Parkinson’s disease Huntington’s disease Amyotrophic lateral sclerosis MicroRNA 



This work was supported in part by grants from the National Natural Science Foundation of China (81000544, 81171209, 81371406), the Shandong Provincial Natural Science Foundation, China (ZR2010HQ004, ZR2011HZ001), and the Shandong Provincial Outstanding Medical Academic Professional Program.

Conflicts of interest

The authors declare no conflicts of interest.


  1. 1.
    De Jager PL, Bennett DA (2013) An inflection point in gene discovery efforts for neurodegenerative diseases: from syndromic diagnoses toward endophenotypes and the epigenome. JAMA Neurol 70(6):719–726. doi: 10.1001/jamaneurol.2013.275 PubMedCentralPubMedGoogle Scholar
  2. 2.
    Cooper-Knock J, Kirby J, Ferraiuolo L, Heath PR, Rattray M, Shaw PJ (2012) Gene expression profiling in human neurodegenerative disease. Nat Rev Neurol 8(9):518–530. doi: 10.1038/nrneurol.2012.156 PubMedGoogle Scholar
  3. 3.
    Nelson PT, Keller JN (2007) RNA in brain disease: no longer just “the messenger in the middle”. J Neuropathol Exp Neurol 66(6):461–468. doi: 10.1097/01.jnen.0000240474.27791.f3 PubMedGoogle Scholar
  4. 4.
    Pearson H (2006) Genetics: what is a gene? Nature 441(7092):398–401. doi: 10.1038/441398a PubMedGoogle Scholar
  5. 5.
    Nelson PT, Wang WX, Rajeev BW (2008) MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 18(1):130–138. doi: 10.1111/j.1750-3639.2007.00120.x PubMedCentralPubMedGoogle Scholar
  6. 6.
    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(5):843–854PubMedGoogle Scholar
  7. 7.
    Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294(5543):853–858. doi: 10.1126/science.1064921 PubMedGoogle Scholar
  8. 8.
    Kapsimali M, Kloosterman WP, de Bruijn E, Rosa F, Plasterk RH, Wilson SW (2007) MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol 8(8):R173. doi: 10.1186/gb-2007-8-8-r173 PubMedCentralPubMedGoogle Scholar
  9. 9.
    Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, Timmusk T, Sipione S, Cattaneo E (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 293(5529):493–498. doi: 10.1126/science.1059581 PubMedGoogle Scholar
  10. 10.
    Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S (2008) A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Hum Mol Genet 17(19):3030–3042. doi: 10.1093/hmg/ddn201 PubMedCentralPubMedGoogle Scholar
  11. 11.
    Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K, Haas J, Ruprecht K, Paul F, Stahler C, Lang CJ, Meder B, Bartfai T, Meese E, Keller A (2013) A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 14(7):R78. doi: 10.1186/gb-2013-14-7-r78 PubMedCentralPubMedGoogle Scholar
  12. 12.
    Tan L, Yu JT, Liu QY, Tan MS, Zhang W, Hu N, Wang YL, Sun L, Jiang T (2013) Circulating miR-125b as a biomarker of Alzheimer’s disease. J Neurol Sci. doi: 10.1016/j.jns.2013.10.002 Google Scholar
  13. 13.
    Geekiyanage H, Jicha GA, Nelson PT, Chan C (2012) Blood serum miRNA: non-invasive biomarkers for Alzheimer’s disease. Exp Neurol 235(2):491–496. doi: 10.1016/j.expneurol.2011.11.026 PubMedCentralPubMedGoogle Scholar
  14. 14.
    Cardo LF, Coto E, de Mena L, Ribacoba R, Moris G, Menendez M, Alvarez V (2013) Profile of microRNAs in the plasma of Parkinson’s disease patients and healthy controls. J Neurol 260(5):1420–1422. doi: 10.1007/s00415-013-6900-8 PubMedGoogle Scholar
  15. 15.
    Li MM, Li XM, Zheng XP, Yu JT, Tan L (2013) MicroRNAs dysregulation in epilepsy. Brain Res. doi: 10.1016/j.brainres.2013.09.049 Google Scholar
  16. 16.
    Tan L, Yu JT, Hu N (2013) Non-coding RNAs in Alzheimer’s disease. Mol Neurobiol 47(1):382–393. doi: 10.1007/s12035-012-8359-5 PubMedGoogle Scholar
  17. 17.
    Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN (2004) MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23(20):4051–4060. doi: 10.1038/sj.emboj.7600385 PubMedCentralPubMedGoogle Scholar
  18. 18.
    Borchert GM, Lanier W, Davidson BL (2006) RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13(12):1097–1101. doi: 10.1038/nsmb1167 PubMedGoogle Scholar
  19. 19.
    Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432(7014):235–240. doi: 10.1038/nature03120 PubMedGoogle Scholar
  20. 20.
    Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293(5531):834–838. doi: 10.1126/science.1062961 PubMedGoogle Scholar
  21. 21.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297PubMedGoogle Scholar
  22. 22.
    Peters L, Meister G (2007) Argonaute proteins: mediators of RNA silencing. Mol Cell 26(5):611–623. doi: 10.1016/j.molcel.2007.05.001 PubMedGoogle Scholar
  23. 23.
    Hammond SM, Bernstein E, Beach D, Hannon GJ (2000) An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 404(6775):293–296. doi: 10.1038/35005107 PubMedGoogle Scholar
  24. 24.
    Elbashir SM, Lendeckel W, Tuschl T (2001) RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev 15(2):188–200PubMedCentralPubMedGoogle Scholar
  25. 25.
    Bian S, Sun T (2011) Functions of noncoding RNAs in neural development and neurological diseases. Mol Neurobiol 44(3):359–373. doi: 10.1007/s12035-011-8211-3 PubMedCentralPubMedGoogle Scholar
  26. 26.
    Hebert SS, De Strooper B (2009) Alterations of the microRNA network cause neurodegenerative disease. Trends Neurosci 32(4):199–206. doi: 10.1016/j.tins.2008.12.003 PubMedGoogle Scholar
  27. 27.
    Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR (2004) Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol 5(9):R68. doi: 10.1186/gb-2004-5-9-r68 PubMedCentralPubMedGoogle Scholar
  28. 28.
    Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (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(3):R13. doi: 10.1186/gb-2004-5-3-r13 PubMedCentralPubMedGoogle Scholar
  29. 29.
    Gao FB (2008) Posttranscriptional control of neuronal development by microRNA networks. Trends Neurosci 31(1):20–26. doi: 10.1016/j.tins.2007.10.004 PubMedCentralPubMedGoogle Scholar
  30. 30.
    Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409(6818):363–366. doi: 10.1038/35053110 PubMedGoogle Scholar
  31. 31.
    Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, Baillie DL, Fire A, Ruvkun G, Mello CC (2001) Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell 106(1):23–34PubMedGoogle Scholar
  32. 32.
    Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A (2007) A microRNA feedback circuit in midbrain dopamine neurons. Science 317(5842):1220–1224. doi: 10.1126/science.1140481 PubMedCentralPubMedGoogle Scholar
  33. 33.
    Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27(3):435–448. doi: 10.1016/j.molcel.2007.07.015 PubMedCentralPubMedGoogle Scholar
  34. 34.
    Papagiannakopoulos T, Kosik KS (2009) MicroRNA-124: micromanager of neurogenesis. Cell Stem Cell 4(5):375–376. doi: 10.1016/j.stem.2009.04.007 PubMedGoogle Scholar
  35. 35.
    Smith P, Al Hashimi A, Girard J, Delay C, Hebert SS (2011) In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs. J Neurochem 116(2):240–247. doi: 10.1111/j.1471-4159.2010.07097.x PubMedGoogle Scholar
  36. 36.
    Bilen J, Liu N, Burnett BG, Pittman RN, Bonini NM (2006) MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Mol Cell 24(1):157–163. doi: 10.1016/j.molcel.2006.07.030 PubMedGoogle Scholar
  37. 37.
    Schaefer A, O’Carroll D, Tan CL, Hillman D, Sugimori M, Llinas R, Greengard P (2007) Cerebellar neurodegeneration in the absence of microRNAs. J Exp Med 204(7):1553–1558. doi: 10.1084/jem.20070823 PubMedCentralPubMedGoogle Scholar
  38. 38.
    Karres JS, Hilgers V, Carrera I, Treisman J, Cohen SM (2007) The conserved microRNA miR-8 tunes atrophin levels to prevent neurodegeneration in Drosophila. Cell 131(1):136–145. doi: 10.1016/j.cell.2007.09.020 PubMedGoogle Scholar
  39. 39.
    Lugli G, Larson J, Martone ME, Jones Y, Smalheiser NR (2005) Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. J Neurochem 94(4):896–905. doi: 10.1111/j.1471-4159.2005.03224.x PubMedGoogle Scholar
  40. 40.
    Okamura K, Hagen JW, Duan H, Tyler DM, Lai EC (2007) The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130(1):89–100. doi: 10.1016/j.cell.2007.06.028 PubMedCentralPubMedGoogle Scholar
  41. 41.
    Zofall M, Grewal SI (2006) RNAi-mediated heterochromatin assembly in fission yeast. Cold Spring Harb Symp Quant Biol 71:487–496. doi: 10.1101/sqb.2006.71.059 PubMedGoogle Scholar
  42. 42.
    Ling SC, Albuquerque CP, Han JS, Lagier-Tourenne C, Tokunaga S, Zhou H, Cleveland DW (2010) ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A 107(30):13318–13323. doi: 10.1073/pnas.1008227107 PubMedCentralPubMedGoogle Scholar
  43. 43.
    Gehrke S, Imai Y, Sokol N, Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466(7306):637–641. doi: 10.1038/nature09191 PubMedCentralPubMedGoogle Scholar
  44. 44.
    Savas JN, Makusky A, Ottosen S, Baillat D, Then F, Krainc D, Shiekhattar R, Markey SP, Tanese N (2008) Huntington’s disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proc Natl Acad Sci U S A 105(31):10820–10825. doi: 10.1073/pnas.0800658105 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Jellinger KA (2009) Recent advances in our understanding of neurodegeneration. J Neural Transm 116(9):1111–1162. doi: 10.1007/s00702-009-0240-y PubMedGoogle Scholar
  46. 46.
    Sonntag KC (2010) MicroRNAs and deregulated gene expression networks in neurodegeneration. Brain Res 1338:48–57. doi: 10.1016/j.brainres.2010.03.106 PubMedGoogle Scholar
  47. 47.
    Patel N, Hoang D, Miller N, Ansaloni S, Huang Q, Rogers JT, Lee JC, Saunders AJ (2008) MicroRNAs can regulate human APP levels. Mol Neurodegener 3:10. doi: 10.1186/1750-1326-3-10 PubMedCentralPubMedGoogle Scholar
  48. 48.
    Hebert SS, Horre K, Nicolai L, Bergmans B, Papadopoulou AS, Delacourte A, De Strooper B (2009) MicroRNA regulation of Alzheimer’s Amyloid precursor protein expression. Neurobiol Dis 33(3):422–428. doi: 10.1016/j.nbd.2008.11.009 PubMedGoogle Scholar
  49. 49.
    Boissonneault V, Plante I, Rivest S, Provost P (2009) MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1. J Biol Chem 284(4):1971–1981. doi: 10.1074/jbc.M807530200 PubMedCentralPubMedGoogle Scholar
  50. 50.
    Wang X, Liu P, Zhu H, Xu Y, Ma C, Dai X, Huang L, Liu Y, Zhang L, Qin C (2009) miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer’s disease, inhibits bcl2 translation. Brain Res Bull 80(4–5):268–273. doi: 10.1016/j.brainresbull.2009.08.006 PubMedGoogle Scholar
  51. 51.
    LeBlanc AC (2005) The role of apoptotic pathways in Alzheimer’s disease neurodegeneration and cell death. Curr Alzheimer Res 2(4):389–402PubMedGoogle Scholar
  52. 52.
    Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT (2008) The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 28(5):1213–1223. doi: 10.1523/JNEUROSCI.5065-07.2008 PubMedCentralPubMedGoogle Scholar
  53. 53.
    Geekiyanage H, Chan C (2011) MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer’s disease. J Neurosci 31(41):14820–14830. doi: 10.1523/JNEUROSCI.3883-11.2011 PubMedCentralPubMedGoogle Scholar
  54. 54.
    Brouwers N, Sleegers K, Van Broeckhoven C (2008) Molecular genetics of Alzheimer’s disease: an update. Ann Med 40(8):562–583. doi: 10.1080/07853890802186905 PubMedGoogle Scholar
  55. 55.
    Jayadev S, Case A, Alajajian B, Eastman AJ, Moller T, Garden GA (2013) Presenilin 2 influences miR146 level and activity in microglia. J Neurochem. doi: 10.1111/jnc.12400 PubMedCentralPubMedGoogle Scholar
  56. 56.
    Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem 127(6):739–749. doi: 10.1111/jnc.12437 PubMedGoogle Scholar
  57. 57.
    Absalon S, Kochanek DM, Raghavan V, Krichevsky AM (2013) MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons. J Neurosci 33(37):14645–14659. doi: 10.1523/JNEUROSCI.1327-13.2013 PubMedCentralPubMedGoogle Scholar
  58. 58.
    Santosh PS, Arora N, Sarma P, Pal-Bhadra M, Bhadra U (2009) Interaction map and selection of microRNA targets in Parkinson’s disease-related genes. J Biomed Biotechnol 2009:363145. doi: 10.1155/2009/363145 Google Scholar
  59. 59.
    Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM (2009) Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci U S A 106(31):13052–13057. doi: 10.1073/pnas.0906277106 PubMedCentralPubMedGoogle Scholar
  60. 60.
    Doxakis E (2010) Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem 285(17):12726–12734. doi: 10.1074/jbc.M109.086827 PubMedCentralPubMedGoogle Scholar
  61. 61.
    Itoh N, Ohta H (2013) Roles of FGF20 in dopaminergic neurons and Parkinson’s disease. Front Mol Neurosci 6:15. doi: 10.3389/fnmol.2013.00015 PubMedCentralPubMedGoogle Scholar
  62. 62.
    Wang G, van der Walt JM, Mayhew G, Li YJ, Zuchner S, Scott WK, Martin ER, Vance JM (2008) Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet 82(2):283–289. doi: 10.1016/j.ajhg.2007.09.021 PubMedCentralPubMedGoogle Scholar
  63. 63.
    Cho HJ, Liu G, Jin SM, Parisiadou L, Xie C, Yu J, Sun L, Ma B, Ding J, Vancraenenbroeck R, Lobbestael E, Baekelandt V, Taymans JM, He P, Troncoso JC, Shen Y, Cai H (2013) MicroRNA-205 regulates the expression of Parkinson’s disease-related leucine-rich repeat kinase 2 protein. Hum Mol Genet 22(3):608–620. doi: 10.1093/hmg/dds470 PubMedCentralPubMedGoogle Scholar
  64. 64.
    Ang SL (2009) Foxa1 and Foxa2 transcription factors regulate differentiation of midbrain dopaminergic neurons. Adv Exp Med Biol 651:58–65PubMedGoogle Scholar
  65. 65.
    Lin W, Metzakopian E, Mavromatakis YE, Gao N, Balaskas N, Sasaki H, Briscoe J, Whitsett JA, Goulding M, Kaestner KH, Ang SL (2009) Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development. Dev Biol 333(2):386–396. doi: 10.1016/j.ydbio.2009.07.006 PubMedGoogle Scholar
  66. 66.
    Kittappa R, Chang WW, Awatramani RB, McKay RD (2007) The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol 5(12):e325. doi: 10.1371/journal.pbio.0050325 PubMedCentralPubMedGoogle Scholar
  67. 67.
    Lin X, Parisiadou L, Gu XL, Wang L, Shim H, Sun L, Xie C, Long CX, Yang WJ, Ding J, Chen ZZ, Gallant PE, Tao-Cheng JH, Rudow G, Troncoso JC, Liu Z, Li Z, Cai H (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 64(6):807–827. doi: 10.1016/j.neuron.2009.11.006 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL (2008) The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. J Neurosci 28(53):14341–14346. doi: 10.1523/JNEUROSCI.2390-08.2008 PubMedCentralPubMedGoogle Scholar
  69. 69.
    Marti E, Pantano L, Banez-Coronel M, Llorens F, Minones-Moyano E, Porta S, Sumoy L, Ferrer I, Estivill X (2010) A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing. Nucleic Acids Res 38(20):7219–7235. doi: 10.1093/nar/gkq575 PubMedCentralPubMedGoogle Scholar
  70. 70.
    Sinha M, Mukhopadhyay S, Bhattacharyya NP (2012) Mechanism(s) of alteration of micro RNA expressions in Huntington’s disease and their possible contributions to the observed cellular and molecular dysfunctions in the disease. Neuromolecular Med 14(4):221–243. doi: 10.1007/s12017-012-8183-0 PubMedGoogle Scholar
  71. 71.
    Zuccato C, Tartari M, Crotti A, Goffredo D, Valenza M, Conti L, Cataudella T, Leavitt BR, Hayden MR, Timmusk T, Rigamonti D, Cattaneo E (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 35(1):76–83. doi: 10.1038/ng1219 PubMedGoogle Scholar
  72. 72.
    Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38(2):228–233. doi: 10.1038/ng1725 PubMedCentralPubMedGoogle Scholar
  73. 73.
    Fox MA, Sanes JR, Borza DB, Eswarakumar VP, Fassler R, Hudson BG, John SW, Ninomiya Y, Pedchenko V, Pfaff SL, Rheault MN, Sado Y, Segal Y, Werle MJ, Umemori H (2007) Distinct target-derived signals organize formation, maturation, and maintenance of motor nerve terminals. Cell 129(1):179–193. doi: 10.1016/j.cell.2007.02.035 PubMedGoogle Scholar
  74. 74.
    Chouliaras L, van den Hove DL, Kenis G, Dela Cruz J, Lemmens MA, van Os J, Steinbusch HW, Schmitz C, Rutten BP (2011) Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus. Brain Behav Immun 25(4):616–623. doi: 10.1016/j.bbi.2010.11.016 PubMedGoogle Scholar
  75. 75.
    Fraga MF (2009) Genetic and epigenetic regulation of aging. Curr Opin Immunol 21(4):446–453. doi: 10.1016/j.coi.2009.04.003 PubMedGoogle Scholar
  76. 76.
    Chuang JC, Jones PA (2007) Epigenetics and microRNAs. Pediatr Res 61(5 Pt 2):24R–29R. doi: 10.1203/pdr.0b013e3180457684 PubMedGoogle Scholar
  77. 77.
    Wang J, Yu JT, Tan MS, Jiang T, Tan L (2013) Epigenetic mechanisms in Alzheimer’s disease: implications for pathogenesis and therapy. Ageing Res Rev 12(4):1024–1041. doi: 10.1016/j.arr.2013.05.003 PubMedGoogle Scholar
  78. 78.
    Chestnut BA, Chang Q, Price A, Lesuisse C, Wong M, Martin LJ (2011) Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci 31(46):16619–16636. doi: 10.1523/JNEUROSCI.1639-11.2011 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F, van Os J, Steinbusch HW, van den Hove DL (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90(4):498–510. doi: 10.1016/j.pneurobio.2010.01.002 PubMedGoogle Scholar
  80. 80.
    Grayson DR, Guidotti A (2013) The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 38(1):138–166. doi: 10.1038/npp.2012.125 PubMedCentralPubMedGoogle Scholar
  81. 81.
    Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, Sultmann H, Lyko F (2007) The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 67(4):1419–1423. doi: 10.1158/0008-5472.CAN-06-4074 PubMedGoogle Scholar
  82. 82.
    Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, Casado S, Suarez-Gauthier A, Sanchez-Cespedes M, Git A, Spiteri I, Das PP, Caldas C, Miska E, Esteller M (2007) Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 67(4):1424–1429. doi: 10.1158/0008-5472.CAN-06-4218 PubMedGoogle Scholar
  83. 83.
    Baer C, Claus R, Frenzel LP, Zucknick M, Park YJ, Gu L, Weichenhan D, Fischer M, Pallasch CP, Herpel E, Rehli M, Byrd JC, Wendtner CM, Plass C (2012) Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia. Cancer Res 72(15):3775–3785. doi: 10.1158/0008-5472.CAN-12-0803 PubMedGoogle Scholar
  84. 84.
    Li J, Harris RA, Cheung SW, Coarfa C, Jeong M, Goodell MA, White LD, Patel A, Kang SH, Shaw C, Chinault AC, Gambin T, Gambin A, Lupski JR, Milosavljevic A (2012) Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome. PLoS Genet 8(5):e1002692. doi: 10.1371/journal.pgen.1002692 PubMedCentralPubMedGoogle Scholar
  85. 85.
    Saito Y, Saito H (2012) MicroRNAs in cancers and neurodegenerative disorders. Front Genet 3:194. doi: 10.3389/fgene.2012.00194 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC (2006) Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 66(3):1277–1281. doi: 10.1158/0008-5472.CAN-05-3632 PubMedGoogle Scholar
  87. 87.
    Liu C, Teng ZQ, Santistevan NJ, Szulwach KE, Guo W, Jin P, Zhao X (2010) Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 6(5):433–444. doi: 10.1016/j.stem.2010.02.017 PubMedCentralPubMedGoogle Scholar
  88. 88.
    Szulwach KE, Li X, Smrt RD, Li Y, Luo Y, Lin L, Santistevan NJ, Li W, Zhao X, Jin P (2010) Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol 189(1):127–141. doi: 10.1083/jcb.200908151 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Vrba L, Jensen TJ, Garbe JC, Heimark RL, Cress AE, Dickinson S, Stampfer MR, Futscher BW (2010) Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One 5(1):e8697. doi: 10.1371/journal.pone.0008697 PubMedCentralPubMedGoogle Scholar
  90. 90.
    Wiklund ED, Kjems J, Clark SJ (2010) Epigenetic architecture and miRNA: reciprocal regulators. Epigenomics 2(6):823–840. doi: 10.2217/epi.10.51 PubMedGoogle Scholar
  91. 91.
    Brait M, Sidransky D (2011) Cancer epigenetics: above and beyond. Toxicol Mech Methods 21(4):275–288. doi: 10.3109/15376516.2011.562671 PubMedCentralPubMedGoogle Scholar
  92. 92.
    Lehmann SM, Kruger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P, Kalin R, Franzoni E, Rybak A, Nguyen D, Veh R, Ninnemann O, Peters O, Nitsch R, Heppner FL, Golenbock D, Schott E, Ploegh HL, Wulczyn FG, Lehnardt S (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15(6):827–835. doi: 10.1038/nn.3113 PubMedGoogle Scholar
  93. 93.
    Wang X, Cao L, Wang Y, Liu N, You Y (2012) Regulation of let-7 and its target oncogenes (Review). Oncol Lett 3(5):955–960. doi: 10.3892/ol.2012.609 PubMedCentralPubMedGoogle Scholar
  94. 94.
    Forman JJ, Legesse-Miller A, Coller HA (2008) A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci U S A 105(39):14879–14884. doi: 10.1073/pnas.0803230105 PubMedCentralPubMedGoogle Scholar
  95. 95.
    Omura N, Li CP, Li A, Hong SM, Walter K, Jimeno A, Hidalgo M, Goggins M (2008) Genome-wide profiling of methylated promoters in pancreatic adenocarcinoma. Cancer Biol Ther 7(7):1146–1156PubMedCentralPubMedGoogle Scholar
  96. 96.
    Vogt M, Munding J, Gruner M, Liffers ST, Verdoodt B, Hauk J, Steinstraesser L, Tannapfel A, Hermeking H (2011) Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch 458(3):313–322. doi: 10.1007/s00428-010-1030-5 PubMedGoogle Scholar
  97. 97.
    Nelson PT, Wang WX (2010) MiR-107 is reduced in Alzheimer’s disease brain neocortex: validation study. J Alzheimers Dis 21(1):75–79. doi: 10.3233/JAD-2010-091603 PubMedCentralPubMedGoogle Scholar
  98. 98.
    Lee KH, Lotterman C, Karikari C, Omura N, Feldmann G, Habbe N, Goggins MG, Mendell JT, Maitra A (2009) Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 9(3):293–301. doi: 10.1159/000186051 PubMedCentralPubMedGoogle Scholar
  99. 99.
    Zhang Y, Yan LX, Wu QN, Du ZM, Chen J, Liao DZ, Huang MY, Hou JH, Wu QL, Zeng MS, Huang WL, Zeng YX, Shao JY (2011) miR-125b is methylated and functions as a tumor suppressor by regulating the ETS1 proto-oncogene in human invasive breast cancer. Cancer Res 71(10):3552–3562. doi: 10.1158/0008-5472.CAN-10-2435 PubMedGoogle Scholar
  100. 100.
    Lukiw WJ (2007) Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport 18(3):297–300. doi: 10.1097/WNR.0b013e3280148e8b PubMedGoogle Scholar
  101. 101.
    Cogswell JPWJ, Taylor IA, Waters M, Shi Y, Cannon B, Kelnar K, Kemppainen J, Brown D, Chen C et al (2008) Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 14:27–41PubMedGoogle Scholar
  102. 102.
    Pogue AI, Cui JG, Li YY, Zhao Y, Culicchia F, Lukiw WJ (2010) Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neurosci Lett 476(1):18–22. doi: 10.1016/j.neulet.2010.03.054 PubMedGoogle Scholar
  103. 103.
    Strum JC, Johnson JH, Ward J, Xie H, Feild J, Hester A, Alford A, Waters KM (2009) MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1. Mol Endocrinol 23(11):1876–1884. doi: 10.1210/me.2009-0117 PubMedGoogle Scholar
  104. 104.
    Soreq H, Wolf Y (2011) NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol Med 17(10):548–555. doi: 10.1016/j.molmed.2011.06.009 PubMedGoogle Scholar
  105. 105.
    Nomura T, Kimura M, Horii T, Morita S, Soejima H, Kudo S, Hatada I (2008) MeCP2-dependent repression of an imprinted miR-184 released by depolarization. Hum Mol Genet 17(8):1192–1199. doi: 10.1093/hmg/ddn011 PubMedGoogle Scholar
  106. 106.
    Goodman RH, Smolik S (2000) CBP/p300 in cell growth, transformation, and development. Genes Dev 14(13):1553–1577PubMedGoogle Scholar
  107. 107.
    Lee ST, Chu K, Im WS, Yoon HJ, Im JY, Park JE, Park KH, Jung KH, Lee SK, Kim M, Roh JK (2011) Altered microRNA regulation in Huntington’s disease models. Exp Neurol 227(1):172–179. doi: 10.1016/j.expneurol.2010.10.012 PubMedGoogle Scholar
  108. 108.
    Johnson R, Buckley NJ (2009) Gene dysregulation in Huntington’s disease: REST, microRNAs and beyond. Neuromolecular Med 11(3):183–199. doi: 10.1007/s12017-009-8063-4 PubMedGoogle Scholar
  109. 109.
    Campos-Melo D, Droppelmann CA, He Z, Volkening K, Strong MJ (2013) Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain 6:26. doi: 10.1186/1756-6606-6-26 PubMedCentralPubMedGoogle Scholar
  110. 110.
    Jiang M, Xiang Y, Wang D, Gao J, Liu D, Liu Y, Liu S, Zheng D (2012) Dysregulated expression of miR-146a contributes to age-related dysfunction of macrophages. Aging Cell 11(1):29–40. doi: 10.1111/j.1474-9726.2011.00757.x PubMedGoogle Scholar
  111. 111.
    Sun Z, Yu JT, Jiang T, Li MM, Tan L, Zhang Q (2013) Genome-wide microRNA profiling of rat hippocampus after status epilepticus induced by amygdala stimulation identifies modulators of neuronal apoptosis. PLoS One 8(10):e78375. doi: 10.1371/journal.pone.0078375 PubMedCentralPubMedGoogle Scholar
  112. 112.
    Li MM, Jiang T, Sun Z, Zhang Q, Tan CC, Yu JT, Tan L (2014) Genome-wide microRNA expression profiles in hippocampus of rats with chronic temporal lobe epilepsy. Sci Rep 4:4734. doi: 10.1038/srep04734 PubMedCentralPubMedGoogle Scholar
  113. 113.
    Tan KS, Armugam A, Sepramaniam S, Lim KY, Setyowati KD, Wang CW, Jeyaseelan K (2009) Expression profile of MicroRNAs in young stroke patients. PLoS One 4(11):e7689. doi: 10.1371/journal.pone.0007689 PubMedCentralPubMedGoogle Scholar
  114. 114.
    Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T (2014) Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer’s disease. J Alzheimers Dis 40(4):1017–1027. doi: 10.3233/JAD-132144 PubMedGoogle Scholar
  115. 115.
    Sheinerman KS, Tsivinsky VG, Abdullah L, Crawford F, Umansky SR (2013) Plasma microRNA biomarkers for detection of mild cognitive impairment: biomarker validation study. Aging (Albany NY) 5(12):925–938Google Scholar
  116. 116.
    Schipper HM, Maes OC, Chertkow HM, Wang E (2007) MicroRNA expression in Alzheimer blood mononuclear cells. Gene Regul Syst Bio 1:263–274PubMedCentralPubMedGoogle Scholar
  117. 117.
    Kiko T, Nakagawa K, Tsuduki T, Furukawa K, Arai H, Miyazawa T (2014) MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer’s disease. J Alzheimers Dis 39(2):253–259. doi: 10.3233/JAD-130932 PubMedGoogle Scholar
  118. 118.
    Margis R, Rieder CR (2011) Identification of blood microRNAs associated to Parkinsons disease. J Biotechnol 152(3):96–101. doi: 10.1016/j.jbiotec.2011.01.023 PubMedGoogle Scholar
  119. 119.
    Soreq L, Salomonis N, Bronstein M, Greenberg DS, Israel Z, Bergman H, Soreq H (2013) Small RNA sequencing-microarray analyses in Parkinson leukocytes reveal deep brain stimulation-induced splicing changes that classify brain region transcriptomes. Front Mol Neurosci 6:10. doi: 10.3389/fnmol.2013.00010 PubMedCentralPubMedGoogle Scholar
  120. 120.
    Martins M, Rosa A, Guedes LC, Fonseca BV, Gotovac K, Violante S, Mestre T, Coelho M, Rosa MM, Martin ER, Vance JM, Outeiro TF, Wang L, Borovecki F, Ferreira JJ, Oliveira SA (2011) Convergence of miRNA expression profiling, alpha-synuclein interacton and GWAS in Parkinson’s disease. PLoS One 6(10):e25443. doi: 10.1371/journal.pone.0025443 PubMedCentralPubMedGoogle Scholar
  121. 121.
    Gaughwin PM, Ciesla M, Lahiri N, Tabrizi SJ, Brundin P, Bjorkqvist M (2011) Hsa-miR-34b is a plasma-stable microRNA that is elevated in pre-manifest Huntington’s disease. Hum Mol Genet 20(11):2225–2237. doi: 10.1093/hmg/ddr111 PubMedGoogle Scholar
  122. 122.
    De Felice B, Guida M, Coppola C, De Mieri G, Cotrufo R (2012) A miRNA signature in leukocytes from sporadic amyotrophic lateral sclerosis. Gene 508(1):35–40. doi: 10.1016/j.gene.2012.07.058 PubMedGoogle Scholar
  123. 123.
    Toivonen JM, Manzano R, Olivan S, Zaragoza P, Garcia-Redondo A, Osta R (2014) MicroRNA-206: a potential circulating biomarker candidate for amyotrophic lateral sclerosis. PLoS One 9(2):e89065. doi: 10.1371/journal.pone.0089065 PubMedCentralPubMedGoogle Scholar
  124. 124.
    Zhang Y, Friedlander RM (2011) Using non-coding small RNAs to develop therapies for Huntington’s disease. Gene Ther 18(12):1139–1149. doi: 10.1038/gt.2011.170 PubMedGoogle Scholar
  125. 125.
    Friedlander MR, Lizano E, Houben AJ, Bezdan D, Banez-Coronel M, Kudla G, Mateu-Huertas E, Kagerbauer B, Gonzalez J, Chen KC, Leproust EM, Marti E, Estivill X (2014) Evidence for the biogenesis of more than 1,000 novel human microRNAs. Genome Biol 15(4):R57. doi: 10.1186/gb-2014-15-4-r57 PubMedCentralPubMedGoogle Scholar
  126. 126.
    Burgos K, Malenica I, Metpally R, Courtright A, Rakela B, Beach T, Shill H, Adler C, Sabbagh M, Villa S, Tembe W, Craig D, Van Keuren-Jensen K (2014) Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer’s and Parkinson’s diseases correlate with disease status and features of pathology. PLoS One 9(5):e94839. doi: 10.1371/journal.pone.0094839 PubMedCentralPubMedGoogle Scholar
  127. 127.
    Ishtiaq M, Campos-Melo D, Volkening K, Strong MJ (2014) Analysis of novel NEFL mRNA targeting microRNAs in amyotrophic lateral sclerosis. PLoS One 9(1):e85653. doi: 10.1371/journal.pone.0085653 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.College of Medicine and PharmaceuticsOcean University of ChinaQingdaoChina
  2. 2.Department of Neurology, Qingdao Municipal Hospital, School of MedicineQingdao UniversityQingdaoChina

Personalised recommendations