BELLEĞİN EPİGENETİK DÜZENLENMESİ: MİKRORNA’LARIN ROLÜ

Abstract

“MikroRNA(miRNA)’lar” kodlanmayan RNA’lar sınıfına ait moleküller olup, protein sentezinin transkripsiyon sonrası (posttranskripsiyonel) düzenleyicileri olarak tanımlanırlar. Bu posttranskripsiyonel düzenlemenin neredeyse tüm biyolojik süreçlerde rol oynadığı düşünülmektedir. Son zamanlarda miRNA aracılı bu regülasyonun, aktivite bağımlı gen ekspresyonunun yer aldığı öğrenme ve bellek oluşumu için de kritik olduğu anlaşılmıştır. Bu endojen RNA’ların sadece öğrenme ve bellek gibi normal beyin fonksiyonlarında değil, aynı zamanda bilişsel işlevlerin etkilendiği çok sayıda nörodejeneratif hastalığın fizyopatolojisinde de işe karıştığı gösterilmiştir. Bu derlemede miRNA’ların sinaptik plastisitedeki rolleri ve bazı nörodejeneratif hastalıklarla ilişkileri ele alınmıştır. Nöral plastisitede miRNA’ların rollerinin tam olarak anlaşılması, bellek fonksiyonlarının bozulduğu nörolojik hastalıklar için genetik tedavilerin ve yeni teşhis yöntemlerinin gelişimine kapı açabilecektir.”

Keywords

• mikroRNA, bellek, nörodejeneratif hastalıklar

The Epıgenetıc Regulatıon Of Memory: The Role Of Mıcrornas

Abstract

“MicroRNAs (miRNAs)” are a class of non-coding RNAs defined as posttranscriptional regulators of protein synthesis. It is believed that this posttranscriptional regulation has been implicated in virtually all aspects of biological processes. Recently, it has been understood that miRNA-mediated regulation is critical for learning and memory formation which requires activity-dependent gene expression. Emerging evidence indicates that these endogenous RNAs are involved in not only normal brain functions such as learning and memory, but also the pathophysiology of many neurodegenerative diseases in which cognitive functions are influenced. In this review, the roles of miRNAs in synaptic plasticity and their relation to some neurodegenerative diseases are discussed. With further elaboration of the role of miRNAs in neural plasticity, the door will be opened for the development of new diagnostic tests and genetic therapies for neurodegenerative diseases in which memory functions are impaired.”

Keywords

• microRNA, memory, neurodegenerative disease

References

1. 1. Benington JH, Frank MG. Cellular and molecular connections between sleep and synaptic plasticity. Prog Neurobiol 2003; 69:71-101.
2. 2. Davis HP, Squire LR. Protein synthesis and memory: a review. Psychol Bull 1984; 96:518-559.
3. 3. Sutton MA, Schuman EM. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 2006; 127:49-58.
4. 4. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116:281-297.
5. 5. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 2009; 10:126-139.
6. 6. Bak M, Silahtaroglu A, Moller M, et al. MicroRNA expression in the adult mouse central nervous system. RNA 2008; 14:432-444.
7. 7. Lugli G, Larson J, Demars MP, Smalheiser NR. Primary microRNA precursor transcripts are localized at post-synaptic densities in adult mouse forebrain. J Neurochem 2012; 123:459-466.
8. 8. Li S, Patel DJ. Drosha and Dicer: Slicers cut from the same cloth. Cell Res 2016; 26:511-512.

9. 9. Barbee SA, Estes PS, Cziko AM, et al. FMRPcontaining neuronal RNPs are structurally and functionally related to somatic P bodies. Neuron 2006; 52:997-1009.
10. 10. Kim J, Krichevsky A, Grad Y, et al. Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc Natl Acad Sci U S A 2004; 101:360-36.
11. 11. Redondo RL, Morris RG. Making memories last: the synaptic tagging and capture hypothesis. Nat Rev Neurosci 2011; 12:17-30.
12. 12. Junn E, Mouradian MM. MicroRNAs in Neurodegenerative Diseases and Their Therapeutic Potential. Pharmacol Ther 2012; 133:142-150.
13. 13. Bredy TW, Lin Q, Wei W, Baker-Andresen D, Mattick JS. MicroRNA regulation of neural plasticity and memory. Neurobiol Learn Mem 2011; 96:89- 94.
14. 14. Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 2006; 13:1097-1101.
15. 15. Yi R, Qin Y, Macara IG, Cullen BR. Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 2003; 17:3011- 3016.
16. 16. Lee YS, Nakahara K, Pham JW, et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/ miRNA silencing pathways. Cell 2004; 117:69-81.
17. 17. Lin S and Gregory RI. MicroRNA biogenesis pathways in cancer. Nature Reviews Cancer 2015; 15:321-333.
18. 18. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136:215-233.
19. 19. Wanet A, Tacheny A, Arnould T, Renard P. miR212/132 expression and functions: within and beyond the neuronal compartment. Nucleic Acids Res 2012; 40:4742-4753.
20. 20. Vo N, Klein ME, Varlamova O, et al. A cAMPresponse element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A 2005; 102:16426-16431.
21. 21. Wayman GA, Davare M, Ando H, et al. An activityregulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci 2008; 105:9093-9098.
22. 22. Nudelman AS, DiRocco DP, Lambert TJ, et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus 2010; 20:492-498.
23. 23. Mellios N, Sugihara H, Castro J, et al. miR-132, an experience-dependent microRNA, is essential for visual cortex plasticity. Nat Neurosci 2011; 14:1240-1242.
24. 24. Hansen KF, Karelina K, Sakamoto K, et al. miRNA132: a dynamic regulator of cognitive capacity. Brain Struct Funct 2013; 218:817-831.
25. 25. Jimenez-Mateos EM, Bray I, Sanz-Rodriguez A, et al. miRNA Expression profile after status epilepticus and hippocampal neuroprotection by targeting miR -132. Am J Pathol 2011; 179:2519-2532.
26. 26. Dhar M, Zhu M, Impey S, et al. Leptin induces hippocampal synaptogenesis via CREB-regulated microRNA-132 suppression of p250GAP. Mol Endocrinol 2014; 28:1073-1087.
27. 27. Fan G, Hutnick L. Methyl- CpG binding proteins in the nervous system. Cell Res 2005; 15:255-261.
28. 28. Adkins NL, Georgel PT. MeCP2: structure and function. Biochem Cell Biol 2011; 89:1-11
29. 30. Hernandez-Rapp J, Smith PY, Filali M, et al. Memory formation and retention are affected in adult miR132/212 knockout mice. Behav Brain Res 2015; 287:15-26.
30. 31. Hansen KF, Sakamoto K, Aten S, et al. Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome. Learn Mem 2016; 23:61-71.
31. 32. Jasińska M, Miłek J, Cymerman IA, Łęski S, Kaczmarek L, Dziembowska M. miR-132 Regulates Dendritic Spine Structure by Direct Targeting of Matrix Metalloproteinase 9 mRNA. Mol Neurobiol 2016; 53:4701-4712.
32. 33. Eacker SM, Keuss MJ, Berezikov E, Dawson VL, Dawson TM. Neuronal activity regulates hippocampal miRNA expression. PloS One 2011; 6:e25068.
33. 34. Åkerblom M, Sachdeva R, Barde I, et al. MicroRNA124 is a subventricular zone neuronal fate determinant. J Neurosci 2012; 32:8879-8889.
34. 35. Rajasethupathy P, Fiumara F, Sheridan R, et al. Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 2009; 63:803-817.
35. 36. Yang Y, Shu X, Liu D, et al. EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 2012; 73:774-788.
36. 37. Motti D, Bixby JL, Lemmon VP. MicroRNAs and neuronal development. Semin Fetal Neonatal Med 2012; 17:347-352.
37. 38. Giusti SA, Vogl AM, Brockmann MM, et al. MicroRNA-9 controls dendritic development by targeting REST. eLife 2014; 3:1-22.
38. 39. Sim SE, Lim CS, Kim JI, et al. The Brain-Enriched MicroRNA miR-9-3p Regulates Synaptic Plasticity and Memory. J Neurosci 2016; 36:8641-8652.
39. 40. Malmevik J, Petri R, Knauff P, et al. Distinct cognitive effects and underlying transcriptome changes upon inhibition of individual miRNAs in hippocampal neurons. Scientific Reports 2016; 6:1- 14.
40. 41. Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME. A brain-specific microRNA regulates dendritic spine development. Nature 2006; 439: 283-289.
41. 42. Siegel G, Obernosterer G, Fiore R, et al. A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nat Cell Biol 2009; 11:705-716.
42. 43. Griggs EM, Young EJ, Rumbaugh G, Miller CA. MicroRNA-182 regulates amygdala-dependent memory formation. J Neurosci 2013; 33:1734- 1740.
43. 44. Woldemichael BT, Jawaid A, Kremer EA, et al. The microRNA cluster miR-183/96/182 contributes to long-term memory in a protein phosphatase 1- dependent manner. Nat Commun 2016; 25:12594.
44. 45. Edbauer D, Neilson JR, Foster KA, et al. Regulation of synaptic structure and function by FMRPassociated microRNAs miR-125b and miR-132. Neuron 2010; 65:373-384.
45. 46. Lin Q, Wei W, Coelho CM, et al. The brain-specific microRNA miR-128b regulates the formation of fear-extinction memory. Nat Neurosci 2011; 14:1115-1117.
46. 47. Gao J, Wang WY, Mao YW, et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 2010; 466:1105-1109.
47. 48. Fiore R, Khudayberdiev S, Christensen M, et al. Mef2-mediated transcription of the miR379–410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. EMBO J 2009; 28:697-710.
48. 49. Smrt RD, Szulwach KE, Pfeiffer RL, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 2010; 28:1060-1070.
49. 50. Ripke S, Sanders AR, Kendler KS, et al. Genomewide association study identifies five new schizophrenia loci. Nat Genet 2011; 43:969-976.
50. 51. Li Y, Li S, Yan J, et al. miR-182 (microRNA-182) suppression in the hippocampus evokes antidepressant-like effects in rats. Prog Neuropsychopharmacol Biol Psychiatry 2016; 4:96-103.
51. 52. Kocerha J, Faghihi MA, Lopez-Toledano MA, et al. MicroRNA-219 modulates NMDA receptormediated neurobehavioral dysfunction. Proc Natl Acad Sci 2009; 106:3507-3512.
52. 53. Barak B, Shvarts-Serebro I, Modai S, et al. Opposing actions of environmental enrichment and Alzheimer's disease on the expression of hippocampal microRNAs in mouse models. Transl Psychiatry 2013; 3:1-13.
53. 54. Santulli G. microRNA: Medical Evidence From Molecular Biology to Clinical Practice. In: Qiu L, Tan EK, Zeng L (eds), microRNAs and Neurodegenerative Diseases. Springer International Publishing, Switzerland 2015, pp 85- 107.
54. 55. Johnson R, Noble W, Tartaglia GG, Buckley NJ. Neurodegeneration as an RNA disorder. Prog Neurobiol 2012; 99:293-315.
55. 56. Hernandez-Rapp J, Rainone S, Hébert SS. MicroRNAs underlying memory deficits in neurodegenerative disorders. Prog Neuropsychopharmacol Biol Psychiatry 2017;73:79-86.
56. 57. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet 2011; 377:1019-31.
57. 58. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 2015; 77:43-51.
58. 59. Lukiw WJ. Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus. Neuroreport 2007;18:297-300.
59. 60. Wang WX, Rajeev BW, Stromberg AJ, et al. The expression of microRNA miR-107 decreases early in Alzheimer’s disease and may accelerate disease progression through regulation of β-site amyloid precursor protein-cleaving enzyme 1. J Neurosci 2008; 28:1213-1223.
60. 61. Smith P, A Hashimi A, Girard J, Delay C, Hebert SS. In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs. J Neurochem 2011; 116:240-247.
61. 62. 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/beta-secretase expression. Proc Natl Acad Sci U S A 2008; 105:6415-6420.
62. 63. Lee ST, Chu K, Jung KH, et al. miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model. Ann Neurol 2012; 72: 269-277.
63. 64. Müller M, Kuiperij HB, Claassen JA, Küsters B, Verbeek MM. MicroRNAs in Alzheimer’s disease: differential expression in hippocampus and cellfree cerebrospinal fluid. Neurobiol Aging 2014; 35:152-158.
64. 65. Kumar S, Reddy PH. Are circulating microRNAs peripheral biomarkers for Alzheimer's disease? Bio chim Biophys Acta 2016; 1862:1617-1627.
65. 66. Shtilbans A, Henchcliffe C. BiomarkersinParkinson’sdisease: an update. Curr Opin Neurol 2012; 25:460-465.
66. 67. Dawson TM, Dawson VL. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 2003; 302:819-822.
67. 68. Aarsland, D. Cognitive impairment in Parkinson's disease and dementia with Lewy bodies. Parkinsonism Relat Disord 2016; 22:144-148.
68. 69. Kim J, Inoue K, Ishii J, et al. A MicroRNA feedback circuit in midbrain dopamine neurons. Science 2007; 317:1220-1224.
69. 70. Wang W, Kwon EJ, Tsai HL. MicroRNAs in learning, memory, and neurological diseases. Learn Mem 2012; 19:359-368.
70. 71. Minones-Moyano E, Porta S, Escaramís G, et al. MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet 2011; 20:3067-3078.
71. 72. Kabaria S, Choi DC, Chaudhuri AD, Mouradian MM, Junn E. Inhibition of miR-34b and miR-34c enhances α-synuclein expression in Parkinson's disease. FEBS Lett 2015; 589:319-325.
72. 73. Wang H, Ye Y, Zhu Z, et al. MiR-124 Regulates Apoptosis and Autophagy Process in MPTP Model of Parkinson's Disease by Targeting to Bim. Brain Pathol 2016; 26: 167-176.
73. 74. Maciotta S, Meregalli M, Torrente Y. The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci 2013; 7:1-17.
74. 75. Savas JN, Makusky A, Ottosen S, et al. Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proc Natl Acad Sci USA 2008; 105:10820- 10825.
75. 76. Johnson R, Zuccato C, Belyaev ND, et al. A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiol Dis 2008; 29:438- 445.
76. 77. Zuccato C, Tartari M, Crotti A, et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003; 35:76-83.
77. 78. Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL. The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington's disease. J Neurosci 2008; 28:14341 -14346.
78. 79. Jin P, Warren ST. Understanding the molecular basis of fragile X syndrome. Hum Mol Genet 2000; 9:901-908.
79. 80. Campos-Melo D, Droppelmann CA, He Z, Volkening K, Strong MJ. Altered microRNA expression profi le in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain 2013; 6:1 -13.
80. 81. Koval ED, Shaner C, Zhang P, et al. Method for widespread microRNA-155 inhibition prolongs survival in ALSmodel mice. Hum Mol Genet 2013; 22:4127-4135.
81. 82. Henshall DC. MicroRNA and epilepsy: profiling, functions and potential clinical applications. Curr Opin Neurol. 2014; 27:199-205.
82. 83. Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005; 438:685-689.