Advertisement

Journal of Molecular Neuroscience

, Volume 67, Issue 2, pp 235–246 | Cite as

miR-34a in Neurophysiology and Neuropathology

  • Christelle En Lin Chua
  • Bor Luen TangEmail author
Article

Abstract

Epigenetic influence of brain and neuronal function plays key regulatory roles in health and diseases. The microRNA miR-34a is a tumor suppressor transcript, and its loss has been prominently linked to various human cancers, including malignancies of the brain. Interestingly, miR-34a is abundantly expressed in the adult mammalian brain, and emerging evidence has implicated its involvement in a range of neurodevelopmental and neuropathological processes. Developmentally, miR-34a regulates neural stem/progenitor cell differentiation and aspects of neurogenesis. During aging, its elevation is connected to hearing loss and age-related macular degeneration. Pathologically, its elevations during epileptic seizures and ischemic stroke contribute to neuronal injury and death. Inhibition or suppression of miR-34a improved neuronal survival against a variety of neurotoxins implicated in Parkinson’s disease. Its elevation may also play a role in neuronal demise in animal models of Alzheimer’s disease, and suppression of its levels may be generally neuroprotective. The roles and activities of miR-34a in the brain are modulated by factors that control its expression (such as Tp53/73), as well as its downstream target genes (such as the sirtuins SIRT1 and SIRT6) and signaling pathways (such the Notch pathway). We discuss here the known and emerging roles of the miR-34a regulatory network in neurophysiology and neuropathology.

Keywords

miR-34a Alzheimer’s disease Tp53 SIRT1 SIRT6 Neuropathology 

Notes

Acknowledgements

BLT is supported by the NUS Graduate School for Integrative Sciences and Engineering

Conflict of interest

The authors declare that they have no conflict interest.

Supplementary material

12031_2018_1231_MOESM1_ESM.xlsx (173 kb)
ESM 1 (XLSX 173 kb)

References

  1. Adams BD, Parsons C, Slack FJ (2016) The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas. Expert Opin Ther Targets 20:737–753Google Scholar
  2. Agostini M, Tucci P, Killick R, Candi E, Sayan BS, Rivetti di Val Cervo P, Nicotera P, McKeon F, Knight RA, Mak TW, Melino G (2011a) Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets. Proc Natl Acad Sci U S A 108:21093–21098PubMedCentralGoogle Scholar
  3. Agostini M, Tucci P, Steinert JR, Shalom-Feuerstein R, Rouleau M, Aberdam D, Forsythe ID, Young KW, Ventura A, Concepcion CP, Han YC, Candi E, Knight RA, Mak TW, Melino G (2011b) microRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proc Natl Acad Sci U S A 108:21099–21104PubMedCentralGoogle Scholar
  4. Alural B, Ozerdem A, Allmer J, Genc K, Genc S (2015) Lithium protects against paraquat neurotoxicity by NRF2 activation and miR-34a inhibition in SH-SY5Y cells. Front Cell Neurosci 9:209PubMedCentralGoogle Scholar
  5. Aranha MM, Santos DM, Solá S, Steer CJ, Rodrigues CMP (2011) miR-34a regulates mouse neural stem cell differentiation. PLoS One 6:e21396PubMedCentralGoogle Scholar
  6. Avansini SH, Torres FR, Vieira AS, Dogini DB, Rogerio F, Coan AC, Morita ME, Guerreiro MM, Yasuda CL, Secolin R, Carvalho BS, Borges MG, Almeida VS, Araújo PAOR, Queiroz L, Cendes F, Lopes-Cendes I (2018) Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia. Ann Neurol 83:623–635PubMedCentralGoogle Scholar
  7. Azevedo JA, Carter BS, Meng F, Turner DL, Dai M, Schatzberg AF, Barchas JD, Jones EG, Bunney WE, Myers RM, Akil H, Watson SJ, Thompson RC (2016) The microRNA network is altered in anterior cingulate cortex of patients with unipolar and bipolar depression. J Psychiatr Res 82:58–67PubMedCentralGoogle Scholar
  8. Ba Q, Cui C, Wen L, Feng S, Zhou J, Yang K (2015) Schisandrin B shows neuroprotective effect in 6-OHDA-induced Parkinson’s disease via inhibiting the negative modulation of miR-34a on Nrf2 pathway. Biomed Pharmacother 75:165–172Google Scholar
  9. Bai XY, Ma Y, Ding R, Fu B, Shi S, Chen XM (2011) miR-335 and miR-34a promote renal senescence by suppressing mitochondrial antioxidative enzymes. J Am Soc Nephrol 22:1252–1261PubMedCentralGoogle Scholar
  10. Bao TH, Miao W, Han JH, Yin M, Yan Y, Wang WW, Zhu YH (2014) Spontaneous running wheel improves cognitive functions of mouse associated with miRNA expressional alteration in hippocampus following traumatic brain injury. J Mol Neurosci 54:622–629Google Scholar
  11. Bavamian S, Mellios N, Lalonde J, Fass DM, Wang J, Sheridan SD, Madison JM, Zhou F, Rueckert EH, Barker D, Perlis RH, Sur M, Haggarty SJ (2015) Dysregulation of miR-34a links neuronal development to genetic risk factors for bipolar disorder. Mol Psychiatry 20:573–584PubMedCentralGoogle Scholar
  12. Beg MS, Brenner AJ, Sachdev J, Borad M, Kang YK, Stoudemire J, Smith S, Bader AG, Kim S, Hong DS (2017) Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Investig New Drugs 35:180–188Google Scholar
  13. Bhakar AL, Tannis LL, Zeindler C, Russo MP, Jobin C, Park DS, MacPherson S, Barker PA (2002) Constitutive nuclear factor-kappa B activity is required for central neuron survival. J Neurosci 22:8466–8475Google Scholar
  14. Bhatnagar S, Chertkow H, Schipper HM, Yuan Z, Shetty V, Jenkins S, Jones T, Wang E (2014) Increased microRNA-34c abundance in Alzheimer’s disease circulating blood plasma. Front Mol Neurosci 7:2PubMedCentralGoogle Scholar
  15. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, MacDougald OA, Cho KR, Fearon ER (2007) p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol 17:1298–1307Google Scholar
  16. Botta-Orfila T, Morató X, Compta Y, Lozano JJ, Falgàs N, Valldeoriola F, Pont-Sunyer C, Vilas D, Mengual L, Fernández M, Molinuevo JL, Antonell A, Martí MJ, Fernández-Santiago R, Ezquerra M (2014) Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson’s disease. J Neurosci Res 92:1071–1077Google Scholar
  17. Briggs CE, Wang Y, Kong B, Woo TUW, Iyer LK, Sonntag KC (2015) Midbrain dopamine neurons in Parkinson’s disease exhibit a dysregulated miRNA and target-gene network. Brain Res 1618:111–121PubMedCentralGoogle Scholar
  18. Brosel S, Laub C, Averdam A, Bender A, Elstner M (2016) Molecular aging of the mammalian vestibular system. Ageing Res Rev 26:72–80Google Scholar
  19. Bukeirat M, Sarkar SN, Hu H, Quintana DD, Simpkins JW, Ren X (2016) miR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c. J Cereb Blood Flow Metab 36:387–392Google Scholar
  20. Carloni S, Favrais G, Saliba E, Albertini MC, Chalon S, Longini M, Gressens P, Buonocore G, Balduini W (2016) Melatonin modulates neonatal brain inflammation through endoplasmic reticulum stress, autophagy, and miR-34a/silent information regulator 1 pathway. J Pineal Res 61:370–380Google Scholar
  21. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT (2007) Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26:745–752PubMedCentralGoogle Scholar
  22. Chang JR, Mukerjee R, Bagashev A, Del Valle L, Chabrashvili T, Hawkins BJ, He JJ, Sawaya BE (2011a) HIV-1 tat protein promotes neuronal dysfunction through disruption of microRNAs. J Biol Chem 286:41125–41134PubMedCentralGoogle Scholar
  23. Chang SJ, Weng SL, Hsieh JY, Wang TY, Chang MDT, Wang HW (2011b) MicroRNA-34a modulates genes involved in cellular motility and oxidative phosphorylation in neural precursors derived from human umbilical cord mesenchymal stem cells. BMC Med Genet 4:65Google Scholar
  24. Chen X, Zhou JY, Zhou JY (2014) microRNA-34a: role in cancer and cardiovascular disease. Curr Drug Targets 15:361–373Google Scholar
  25. Chim CS, Wong KY, Qi Y, Loong F, Lam WL, Wong LG, Jin DY, Costello JF, Liang R (2010) Epigenetic inactivation of the miR-34a in hematological malignancies. Carcinogenesis 31:745–750Google Scholar
  26. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P, Zhong Y, Kim SY, Bennett MJ, Chen C, Ozturk A, Hicks GG, Hannon GJ, He L (2011) miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 13:1353–1360PubMedCentralGoogle Scholar
  27. Choi SY, Pang K, Kim JY, Ryu JR, Kang H, Liu Z, Kim WK, Sun W, Kim H, Han K (2015) Post-transcriptional regulation of SHANK3 expression by microRNAs related to multiple neuropsychiatric disorders. Mol Brain 8:74PubMedCentralGoogle Scholar
  28. Concepcion CP, Han YC, Mu P, Bonetti C, Yao E, D’Andrea A, Vidigal JA, Maughan WP, Ogrodowski P, Ventura A (2012) Intact p53-dependent responses in miR-34-deficient mice. PLoS Genet 8:e1002797PubMedCentralGoogle Scholar
  29. Cosín-Tomás M, Antonell A, Lladó A, Alcolea D, Fortea J, Ezquerra M, Lleó A, Martí MJ, Pallàs M, Sanchez-Valle R, Molinuevo JL, Sanfeliu C, Kaliman P (2016) Plasma miR-34a-5p and miR-545-3p as early biomarkers of Alzheimer’s disease: potential and limitations. Mol NeurobiolGoogle Scholar
  30. Cuevas-Diaz Duran R, Wei H, Wu JQ (2017) Single-cell RNA-sequencing of the brain. Clin Transl Med 6:20PubMedCentralGoogle Scholar
  31. Cui H, Ge J, Xie N, Banerjee S, Zhou Y, Antony VB, Thannickal VJ, Liu G (2017a) miR-34a inhibits lung fibrosis by inducing lung fibroblast senescence. Am J Respir Cell Mol Biol 56:168–178PubMedCentralGoogle Scholar
  32. Cui M, Xiao H, Li Y, Dong J, Luo D, Li H, Feng G, Wang H, Fan S (2017b) Total abdominal irradiation exposure impairs cognitive function involving miR-34a-5p/BDNF axis. Biochim Biophys Acta 1863:2333–2341PubMedCentralGoogle Scholar
  33. Danka Mohammed CP, Park JS, Nam HG, Kim K (2017) MicroRNAs in brain aging. Mech Ageing Dev 168:3–9Google Scholar
  34. Deshmukh P, Unni S, Krishnappa G, Padmanabhan B (2017) The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev 9:41–56Google Scholar
  35. Di Bari M, Bevilacqua V, De Jaco A, Laneve P, Piovesana R, Trobiani L, Talora C, Caffarelli E, Tata AM (2018) Mir-34a-5p mediates cross-talk between M2 muscarinic receptors and Notch-1/EGFR pathways in U87MG glioblastoma cells: implication in cell proliferation. Int J Mol Sci 19:Google Scholar
  36. Dias BG, Goodman JV, Ahluwalia R, Easton AE, Andero R, Ressler KJ (2014) Amygdala-dependent fear memory consolidation via miR-34a and notch signaling. Neuron 83:906–918PubMedCentralGoogle Scholar
  37. Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS (2013) Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem 127:739–749Google Scholar
  38. Do MT, Kim HG, Choi JH, Jeong HG (2014) Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1α/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic Biol Med 74:21–34Google Scholar
  39. Duan W, Xu Y, Dong Y, Cao L, Tong J, Zhou X (2013) Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway. J Radiat Res (Tokyo) 54:611–619Google Scholar
  40. Dunlop EA, Tee AR (2014) mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 36:121–129Google Scholar
  41. El-Mir MY, Detaille D, R-Villanueva G, Delgado-Esteban M, Guigas B, Attia S, Fontaine E, Almeida A, Leverve X (2008) Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 34:77–87Google Scholar
  42. Emmanouil M, Taoufik E, Tseveleki V, Vamvakas SS, Probert L (2011) A role for neuronal NF-κB in suppressing neuroinflammation and promoting neuroprotection in the CNS. Adv Exp Med Biol 691:575–581Google Scholar
  43. Farooqi AA, Fayyaz S, Shatynska-Mytsyk I, Javed Z, Jabeen S, Yaylim I, Gasparri ML, Panici PB (2016) Is miR-34a a well-equipped swordsman to conquer temple of molecular oncology? Chem Biol Drug Des 87:321–334Google Scholar
  44. Fineberg SK, Datta P, Stein CS, Davidson BL (2012) MiR-34a represses Numbl in murine neural progenitor cells and antagonizes neuronal differentiation. PLoS One 7:e38562PubMedCentralGoogle Scholar
  45. Gao H, Zhao H, Xiang W (2013) Expression level of human miR-34a correlates with glioma grade and prognosis. J Neuro-Oncol 113:221–228Google Scholar
  46. Genovese G, Ergun A, Shukla SA, Campos B, Hanna J, Ghosh P, Quayle SN, Rai K, Colla S, Ying H, Wu CJ, Sarkar S, Xiao Y, Zhang J, Zhang H, Kwong L, Dunn K, Wiedemeyer WR, Brennan C, Zheng H, Rimm DL, Collins JJ, Chin L (2012) microRNA regulatory network inference identifies miR-34a as a novel regulator of TGF-β signaling in glioblastoma. Cancer Discov 2:736–749PubMedCentralGoogle Scholar
  47. Gorter JA, Iyer A, White I, Colzi A, van Vliet EA, Sisodiya S, Aronica E (2014) Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol Dis 62:508–520Google Scholar
  48. Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, Purow B, Abounader R (2010) microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 9:1031–1036PubMedCentralGoogle Scholar
  49. Gui Y, Liu H, Zhang L, Lv W, Hu X (2015) Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 6:37043–37053PubMedCentralGoogle Scholar
  50. Gulino A, Di Marcotullio L, Screpanti I (2010) The multiple functions of numb. Exp Cell Res 316:900–906Google Scholar
  51. Halimi M, Shahabi A, Moslemi D, Parsian H, Asghari SM, Sariri R, Yeganeh F, Zabihi E (2016) Human serum miR-34a as an indicator of exposure to ionizing radiation. Radiat Environ Biophys 55:423–429Google Scholar
  52. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134PubMedCentralGoogle Scholar
  53. Helzner EP, Contrera KJ (2016) Type 2 diabetes and hearing impairment. Curr Diab Rep 16:3Google Scholar
  54. Heng JIT, Nguyen L, Castro DS, Zimmer C, Wildner H, Armant O, Skowronska-Krawczyk D, Bedogni F, Matter JM, Hevner R, Guillemot F (2008) Neurogenin 2 controls cortical neuron migration through regulation of Rnd2. Nature 455:114–118Google Scholar
  55. Henshall DC (2013) MicroRNAs in the pathophysiology and treatment of status epilepticus. Front Mol Neurosci 6:37PubMedCentralGoogle Scholar
  56. Hermeking H (2010) The miR-34 family in cancer and apoptosis. Cell Death Differ 17:193–199Google Scholar
  57. Horst CH, Titze-de-Almeida R, Titze-de-Almeida SS (2017) The involvement of Eag1 potassium channels and miR-34a in rotenone-induced death of dopaminergic SH-SY5Y cells. Mol Med Rep 15:1479–1488PubMedCentralGoogle Scholar
  58. Hou Q, Zhou L, Tang J, Ma N, Xu A, Tang J, Zheng D, Chen X, Chen F, Dong XD, Tu L (2016) LGR4 is a direct target of microRNA-34a and modulates the proliferation and migration of retinal pigment epithelial ARPE-19 cells. PLoS One 11:e0168320PubMedCentralGoogle Scholar
  59. Hu K, Xie YY, Zhang C, Ouyang DS, Long HY, Sun DN, Long LL, Feng L, Li Y, Xiao B (2012) MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus. BMC Neurosci 13:115PubMedCentralGoogle Scholar
  60. Huang Q, Ou Y, Xiong H, Yang H, Zhang Z, Chen S, Ye Y, Zheng Y (2017) The miR-34a/Bcl-2 pathway contributes to auditory cortex neuron apoptosis in age-related hearing loss. Audiol Neurotol 22:96–103Google Scholar
  61. Jauhari A, Singh T, Singh P, Parmar D, Yadav S (2018) Regulation of miR-34 family in neuronal development. Mol Neurobiol 55:936–945Google Scholar
  62. Jia L, Chopp M, Wang L, Lu X, Zhang Y, Szalad A, Zhang ZG (2018) MiR-34a regulates axonal growth of dorsal root ganglia neurons by targeting FOXP2 and VAT1 in postnatal and adult mouse. Mol NeurobiolGoogle Scholar
  63. Jian C, Lu M, Zhang Z, Liu L, Li X, Huang F, Xu N, Qin L, Zhang Q, Zou D (2017) miR-34a knockout attenuates cognitive deficits in APP/PS1 mice through inhibition of the amyloidogenic processing of APP. Life Sci 182:104–111Google Scholar
  64. Jung ES, Choi H, Song H, Hwang YJ, Kim A, Ryu H, Mook-Jung I (2016) p53-dependent SIRT6 expression protects Aβ42-induced DNA damage. Sci Rep 6:25628PubMedCentralGoogle Scholar
  65. Kaluski S, Portillo M, Besnard A, Stein D, Einav M, Zhong L, Ueberham U, Arendt T, Mostoslavsky R, Sahay A, Toiber D (2017) Neuroprotective functions for the histone deacetylase SIRT6. Cell Rep 18:3052–3062PubMedCentralGoogle Scholar
  66. Kan AA, van Erp S, Derijck AAHA, de Wit M, Hessel EVS, O’Duibhir E, de Jager W, Van Rijen PC, Gosselaar PH, de Graan PNE, Pasterkamp RJ (2012) Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response. Cell Mol Life Sci 69:3127–3145PubMedCentralGoogle Scholar
  67. Khanna A, Muthusamy S, Liang R, Sarojini H, Wang E (2011) Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging 3:223–236PubMedCentralGoogle Scholar
  68. 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 39:253–259Google Scholar
  69. Kim AH, Reimers M, Maher B, Williamson V, McMichael O, McClay JL, van den Oord EJCG, Riley BP, Kendler KS, Vladimirov VI (2010) MicroRNA expression profiling in the prefrontal cortex of individuals affected with schizophrenia and bipolar disorders. Schizophr Res 124:183–191PubMedCentralGoogle Scholar
  70. Kofman AV, Kim J, Park SY, Dupart E, Letson C, Bao Y, Ding K, Chen Q, Schiff D, Larner J, Abounader R (2013) microRNA-34a promotes DNA damage and mitotic catastrophe. Cell Cycle 12:3500–3511PubMedCentralGoogle Scholar
  71. Kou X, Liu X, Chen X, Li J, Yang X, Fan J, Yang Y, Chen N (2016) Ampelopsin attenuates brain aging of D-gal-induced rats through miR-34a-mediated SIRT1/mTOR signal pathway. Oncotarget 7:74484–74495PubMedCentralGoogle Scholar
  72. Lacombe J, Zenhausern F (2017) Emergence of miR-34a in radiation therapy. Crit Rev Oncol Hematol 109:69–78Google Scholar
  73. Li L (2014) Regulatory mechanisms and clinical perspectives of miR-34a in cancer. J Cancer Res Ther 10:805–810Google Scholar
  74. Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R (2009) MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 69:7569–7576PubMedCentralGoogle Scholar
  75. Li X, Khanna A, Li N, Wang E (2011a) Circulatory miR34a as an RNAbased, noninvasive biomarker for brain aging. Aging 3:985–1002PubMedCentralGoogle Scholar
  76. Li WB, Ma MW, Dong LJ, Wang F, Chen LX, Li XR (2011b) MicroRNA-34a targets notch1 and inhibits cell proliferation in glioblastoma multiforme. Cancer Biol Ther 12:477–483Google Scholar
  77. Li QL, Zhang HY, Qin YJ, Meng QL, Yao XL, Guo HK (2016) MicroRNA-34a promoting apoptosis of human lens epithelial cells through down-regulation of B-cell lymphoma-2 and silent information regulator. Int J Ophthalmol 9:1555–1560PubMedCentralGoogle Scholar
  78. Li LH, Tu QY, Deng XH, Xia J, Hou DR, Guo K, Zi XH (2017) Mutant presenilin2 promotes apoptosis through the p53/miR-34a axis in neuronal cells. Brain Res 1662:57–64Google Scholar
  79. Liang TY, Lou JY (2016) Increased expression of mir-34a-5p and clinical association in acute ischemic stroke patients and in a rat model. Med Sci Monit 22:2950–2955PubMedCentralGoogle Scholar
  80. Lin Y, Shen J, Li D, Ming J, Liu X, Zhang N, Lai J, Shi M, Ji Q, Xing Y (2017) MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling. Gen Comp Endocrinol 246:63–70Google Scholar
  81. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, Wiggins JF, Bader AG, Fagin R, Brown D, Tang DG (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211–215PubMedCentralGoogle Scholar
  82. Liu N, Landreh M, Cao K, Abe M, Hendriks GJ, Kennerdell JR, Zhu Y, Wang LS, Bonini NM (2012) The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482:519–523PubMedCentralGoogle Scholar
  83. Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Körner H, Knyazev P, Diebold J, Hermeking H (2008) Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 7:2591–2600Google Scholar
  84. Mao S, Sun Q, Xiao H, Zhang C, Li L (2015) Secreted miR-34a in astrocytic shedding vesicles enhanced the vulnerability of dopaminergic neurons to neurotoxins by targeting Bcl-2. Protein Cell 6:529–540PubMedCentralGoogle Scholar
  85. Mattson MP, Meffert MK (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 13:852–860Google Scholar
  86. McCarthy MJ, Le Roux MJ, Wei H, Beesley S, Kelsoe JR, Welsh DK (2016) Calcium channel genes associated with bipolar disorder modulate lithium’s amplification of circadian rhythms. Neuropharmacology 101:439–448Google Scholar
  87. Miñones-Moyano E, Porta S, Escaramís G, Rabionet R, Iraola S, Kagerbauer B, Espinosa-Parrilla Y, Ferrer I, Estivill X, Martí E (2011) MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet 20:3067–3078Google Scholar
  88. Modi PK, Jaiswal S, Sharma P (2016) Regulation of neuronal cell cycle and apoptosis by microRNA 34a. Mol Cell Biol 36:84–94Google Scholar
  89. Mohan M, Kumar V, Lackner AA, Alvarez X (2015) Dysregulated miR-34a-SIRT1-acetyl p65 axis is a potential mediator of immune activation in the colon during chronic simian immunodeficiency virus infection of rhesus macaques. J Immunol 194:291–306Google Scholar
  90. Mollinari C, Racaniello M, Berry A, Pieri M, de Stefano MC, Cardinale A, Zona C, Cirulli F, Garaci E, Merlo D (2015) miR-34a regulates cell proliferation, morphology and function of newborn neurons resulting in improved behavioural outcomes. Cell Death Dis 6:e1622PubMedCentralGoogle Scholar
  91. Morgado AL, Xavier JM, Dionísio PA, Ribeiro MFC, Dias RB, Sebastião AM, Solá S, Rodrigues CMP (2015) MicroRNA-34a modulates neural stem cell differentiation by regulating expression of synaptic and autophagic proteins. Mol Neurobiol 51:1168–1183Google Scholar
  92. Mukerjee R, Chang JR, Del Valle L, Bagashev A, Gayed MM, Lyde RB, Hawkins BJ, Brailoiu E, Cohen E, Power C, Azizi SA, Gelman BB, Sawaya BE (2011) Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders. J Biol Chem 286:34976–34985PubMedCentralGoogle Scholar
  93. Ouyang YB, Stary CM, Yang GY, Giffard R (2013) microRNAs: innovative targets for cerebral ischemia and stroke. Curr Drug Targets 14:90–101PubMedCentralGoogle Scholar
  94. Owczarz M, Budzinska M, Domaszewska-Szostek A, Borkowska J, Polosak J, Gewartowska M, Slusarczyk P, Puzianowska-Kuznicka M (2017) miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans. Exp Biol Med (Maywood) 242:1453–1461Google Scholar
  95. Pang J, Xiong H, Yang H, Ou Y, Xu Y, Huang Q, Lai L, Chen S, Zhang Z, Cai Y, Zheng Y (2016) Circulating miR-34a levels correlate with age-related hearing loss in mice and humans. Exp Gerontol 76:58–67Google Scholar
  96. Potts MB, Lim DA (2012) An old drug for new ideas: metformin promotes adult neurogenesis and spatial memory formation. Cell Stem Cell 11:5–6PubMedCentralGoogle Scholar
  97. Rachmany L, Tweedie D, Rubovitch V, Yu QS, Li Y, Wang JY, Pick CG, Greig NH (2013) Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-α. PLoS One 8:e79837PubMedCentralGoogle Scholar
  98. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M (2007) Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell 26:731–743Google Scholar
  99. Ren X, Engler-Chiurazzi EB, Russell AE, Sarkar SN, Rellick SL, Lewis S, Corbin D, Clapper J, Simpkins JW (2018) MiR-34a and stroke: assessment of non-modifiable biological risk factors in cerebral ischemia. Neurochem IntGoogle Scholar
  100. Rink C, Khanna S (2011) MicroRNA in ischemic stroke etiology and pathology. Physiol Genomics 43:521–528Google Scholar
  101. Rokavec M, Li H, Jiang L, Hermeking H (2014) The p53/miR-34 axis in development and disease. J Mol Cell Biol 6:214–230Google Scholar
  102. Romano GL, Platania CBM, Drago F, Salomone S, Ragusa M, Barbagallo C, Di Pietro C, Purrello M, Reibaldi M, Avitabile T, Longo A, Bucolo C (2017) Retinal and circulating miRNAs in age-related macular degeneration: an in vivo animal and human study. Front Pharmacol 8:168PubMedCentralGoogle Scholar
  103. Rostamian Delavar M, Baghi M, Safaeinejad Z, Kiani-Esfahani A, Ghaedi K, Nasr-Esfahani MH (2018) Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson’s disease. Gene 662:54–65Google Scholar
  104. Roth TN (2015) Aging of the auditory system. Handb Clin Neurol 129:357–373Google Scholar
  105. Roy J, Mallick B (2017) Altered gene expression in late-onset Alzheimer’s disease due to SNPs within 3'UTR microRNA response elements. Genomics 109:177–185Google Scholar
  106. Russell AE, Doll DN, Sarkar SN, Simpkins JW (2016) TNF-α and beyond: rapid mitochondrial dysfunction mediates TNF-α-induced neurotoxicity. J Clin Cell Immunol 7:pii: 467Google Scholar
  107. Saito Y, Nakaoka T, Saito H (2015) microRNA-34a as a therapeutic agent against human cancer. J Clin Med 4:1951–1959PubMedCentralGoogle Scholar
  108. Sano T, Reynolds JP, Jimenez-Mateos EM, Matsushima S, Taki W, Henshall DC (2012) MicroRNA-34a upregulation during seizure-induced neuronal death. Cell Death Dis 3:e287PubMedCentralGoogle Scholar
  109. Sarkar S, Jun S, Rellick S, Quintana DD, Cavendish JZ, Simpkins JW (2016) Expression of microRNA-34a in Alzheimer’s disease brain targets genes linked to synaptic plasticity, energy metabolism, and resting state network activity. Brain Res 1646:139–151PubMedCentralGoogle Scholar
  110. Sasaki A, Udaka Y, Tsunoda Y, Yamamoto G, Tsuji M, Oyamada H, Oguchi K, Mizutani T (2012) Analysis of p53 and miRNA expression after irradiation of glioblastoma cell lines. Anticancer Res 32:4709–4713Google Scholar
  111. Schipper HM, Maes OC, Chertkow HM, Wang E (2007) MicroRNA expression in Alzheimer blood mononuclear cells. Gene Regul Syst Bio 1:263–274PubMedCentralGoogle Scholar
  112. Silber J, Jacobsen A, Ozawa T, Harinath G, Pedraza A, Sander C, Holland EC, Huse JT (2012) miR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and promotes tumorigenesis. PLoS One 7:e33844PubMedCentralGoogle Scholar
  113. Smith-Vikos T, Slack FJ (2012) MicroRNAs and their roles in aging. J Cell Sci 125:7–17PubMedCentralGoogle Scholar
  114. Smit-McBride Z, Forward KI, Nguyen AT, Bordbari MH, Oltjen SL, Hjelmeland LM (2014) Age-dependent increase in miRNA-34a expression in the posterior pole of the mouse eye. Mol Vis 20:1569–1578PubMedCentralGoogle Scholar
  115. Song YJ, Tian XB, Zhang S, Zhang YX, Li X, Li D, Cheng Y, Zhang JN, Kang CS, Zhao W (2011) Temporal lobe epilepsy induces differential expression of hippocampal miRNAs including let-7e and miR-23a/b. Brain Res 1387:134–140Google Scholar
  116. Song HT, Sun XY, Zhang L, Zhao L, Guo ZM, Fan HM, Zhong AF, Niu W, Dai YH, Zhang LY, Shi Z, Liu XP, Lu J (2014) A preliminary analysis of association between the down-regulation of microRNA-181b expression and symptomatology improvement in schizophrenia patients before and after antipsychotic treatment. J Psychiatr Res 54:134–140Google Scholar
  117. Soni K, Choudhary A, Patowary A, Singh AR, Bhatia S, Sivasubbu S, Chandrasekaran S, Pillai B (2013) miR-34 is maternally inherited in Drosophila melanogaster and Danio rerio. Nucleic Acids Res 41:4470–4480PubMedCentralGoogle Scholar
  118. Sun XY, Lu J, Zhang L, Song HT, Zhao L, Fan HM, Zhong AF, Niu W, Guo ZM, Dai YH, Chen C, Ding YF, Zhang LY (2015) Aberrant microRNA expression in peripheral plasma and mononuclear cells as specific blood-based biomarkers in schizophrenia patients. J Clin Neurosci 22:570–574Google Scholar
  119. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H (2007) Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A 104:15472–15477PubMedCentralGoogle Scholar
  120. Thor T, Künkele A, Pajtler KW, Wefers AK, Stephan H, Mestdagh P, Heukamp L, Hartmann W, Vandesompele J, Sadowski N, Becker L, Garrett L, Hölter SM, Horsch M, Calzada-Wack J, Klein-Rodewald T, Racz I, Zimmer A, Beckers J, Neff F, Klopstock T, Antonellis PD, Zollo M, Wurst W, Fuchs H, Gailus-Durner V, Schüller U, de Angelis MH, Eggert A, Schramm A, Schulte JH (2015) MiR-34a deficiency accelerates medulloblastoma formation in vivo. Int J Cancer 136:2293–2303Google Scholar
  121. Truettner JS, Motti D, Dietrich WD (2013) MicroRNA overexpression increases cortical neuronal vulnerability to injury. Brain Res 1533:122–130Google Scholar
  122. Uchino S, Waga C (2015) Novel therapeutic approach for autism spectrum disorder: focus on SHANK3. Curr Neuropharmacol 13:786–792PubMedCentralGoogle Scholar
  123. Van Roosbroeck K, Calin GA (2017) Cancer hallmarks and microRNAs: the therapeutic connection. Adv Cancer Res 135:119–149Google Scholar
  124. Viader A, Chang LW, Fahrner T, Nagarajan R, Milbrandt J (2011) MicroRNAs modulate Schwann cell response to nerve injury by reinforcing transcriptional silencing of dedifferentiation-related genes. J Neurosci 31:17358–17369PubMedCentralGoogle Scholar
  125. 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 80:268–273Google Scholar
  126. Wang Y, Guo F, Pan C, Lou Y, Zhang P, Guo S, Yin J, Deng Z (2012) Effects of low temperatures on proliferation-related signaling pathways in the hippocampus after traumatic brain injury. Exp Biol Med (Maywood) 237:1424–1432Google Scholar
  127. Wang XP, Zhou J, Han M, Chen CB, Zheng YT, He XS, Yuan XP (2017) MicroRNA-34a regulates liver regeneration and the development of liver cancer in rats by targeting notch signaling pathway. Oncotarget 8:13264–13276PubMedCentralGoogle Scholar
  128. Weeraratne SD, Amani V, Neiss A, Teider N, Scott DK, Pomeroy SL, Cho YJ (2011) miR-34a confers chemosensitivity through modulation of MAGE-a and p53 in medulloblastoma. Neuro-Oncology 13:165–175Google Scholar
  129. Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D, Bader AG (2010) Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34. Cancer Res 70:5923–5930PubMedCentralGoogle Scholar
  130. Wirgenes KV, Tesli M, Inderhaug E, Athanasiu L, Agartz I, Melle I, Hughes T, Andreassen OA, Djurovic S (2014) ANK3 gene expression in bipolar disorder and schizophrenia. Br J Psychiatry 205:244–245Google Scholar
  131. Wong SY, Tang BL (2016) SIRT1 as a therapeutic target for Alzheimer’s disease. Rev Neurosci 27:813–825Google Scholar
  132. Wu HZY, Ong KL, Seeher K, Armstrong NJ, Thalamuthu A, Brodaty H, Sachdev P, Mather K (2016) Circulating microRNAs as biomarkers of Alzheimer’s disease: a systematic review. J Alzheimers Dis 49:755–766Google Scholar
  133. Xie W, Wang L, Sheng H, Qiu J, Zhang D, Zhang L, Yang F, Tang D, Zhang K (2017) Metformin induces growth inhibition and cell cycle arrest by upregulating MicroRNA34a in renal Cancer cells. Med Sci Monit 23:29–37PubMedCentralGoogle Scholar
  134. Xiong H, Pang J, Yang H, Dai M, Liu Y, Ou Y, Huang Q, Chen S, Zhang Z, Xu Y, Lai L, Zheng Y (2015) Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss. Neurobiol Aging 36:1692–1701Google Scholar
  135. Xu Y, Chen P, Wang X, Yao J, Zhuang S (2018) miR-34a deficiency in APP/PS1 mice promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors. Neurosci Lett 670:94–104Google Scholar
  136. Yamakuchi M, Lowenstein CJ (2009) MiR-34, SIRT1 and p53: the feedback loop. Cell Cycle 8:712–715Google Scholar
  137. Yamakuchi M, Ferlito M, Lowenstein CJ (2008) miR-34a repression of SIRT1 regulates apoptosis. Proc Natl Acad Sci U S A 105:13421–13426PubMedCentralGoogle Scholar
  138. Yamamura S, Saini S, Majid S, Hirata H, Ueno K, Chang I, Tanaka Y, Gupta A, Dahiya R (2012) MicroRNA-34a suppresses malignant transformation by targeting c-Myc transcriptional complexes in human renal cell carcinoma. Carcinogenesis 33:294–300Google Scholar
  139. Ye YL, Zhu LF, Gao LH, Gong L, He M (2017) Analysis of miR-34a function in brain development and behavior using knockout mouse model. Acta Physiol Sin 69:452–460Google Scholar
  140. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW (2004) Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23:2369–2380PubMedCentralGoogle Scholar
  141. Yin D, Ogawa S, Kawamata N, Leiter A, Ham M, Li D, Doan NB, Said JW, Black KL, Phillip Koeffler H (2013) miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme. Oncogene 32:1155–1163Google Scholar
  142. Zhan J, Qin S, Lu L, Hu X, Zhou J, Sun Y, Yang J, Liu Y, Wang Z, Tan N, Chen J, Zhang C (2016) miR-34a is a common link in both HIV- and antiretroviral therapy-induced vascular aging. Aging 8:3298–3310PubMedCentralGoogle Scholar
  143. Zhang YL, Xing RZ, Luo XB, Xu H, Chang RCC, Zou LY, Liu JJ, Yang XF (2016) Anxiety-like behavior and dysregulation of miR-34a in triple transgenic mice of Alzheimer’s disease. Eur Rev Med Pharmacol Sci 20:2853–2862Google Scholar
  144. Zhao W, Wang P, Ma J, Liu YH, Li Z, Li ZQ, Wang ZH, Chen LY, Xue YX (2015) MiR-34a regulates blood-tumor barrier function by targeting protein kinase Cε. Mol Biol Cell 26:1786–1796PubMedCentralGoogle Scholar
  145. Zhou F, Zhang C, Guan Y, Chen Y, Lu Q, Jie L, Gao H, Du H, Zhang H, Liu Y, Wang X (2018) Screening the expression characteristics of several miRNAs in G93A-SOD1 transgenic mouse: altered expression of miRNA-124 is associated with astrocyte differentiation by targeting Sox2 and Sox9. J Neurochem 145:51–67Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Singapore Nuclear Research and Safety InitiativeNational University of SingaporeSingaporeSingapore
  2. 2.Department of Biochemistry, Yong Loo Lin School of MedicineNational University Health SystemSingaporeSingapore
  3. 3.NUS Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore

Personalised recommendations