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MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy

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Abstract

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene, leading to a defect in the peroxisomal adrenoleukodystrophy protein (ALDP), which inhibits the β-oxidation of very long chain fatty acids (VLCFAs). It is a complex disease where the same mutation in the peroxisomal ABCD1 can lead to clinically diverse phenotypes ranging from the fatal disorder of cerebral ALD (cALD) to mild adult disorder of adrenomyeloneuropathy (AMN). This suggests a role of epigenetic factors/modifier genes in disease progression of X-ALD which is not understood at present. To examine the possible role of microRNA (miRNA) in X-ALD disease mechanisms for differences in cALD and AMN phenotype, we profiled 1008 known miRNA in cALD, AMN, and normal human skin fibroblasts using miScript miRNA PCR array (Qiagen) and selected miRNAs which had differential expression in cALD and AMN fibroblasts. Eleven miRNA which were differentially regulated in cALD and AMN fibroblasts were identified. miR-196a showed a significant differential expression between cALD and AMN and is further characterized for target gene regulation. The predicted role of miR-196a in inhibition of inflammatory signaling factors (IKKα and IKKβ) and ELOVL1 expression suggests the pathological role of altered expression of miR-196a. This study indicates that miR-196a participated in differential regulation of ELOVL1 and inflammatory response between cALD as compared to AMN and may be a possible biomarker to differentiate between cALD and AMN.

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References

  1. Berger J, Gartner J (2006) X-linked adrenoleukodystrophy: clinical, biochemical and pathogenetic aspects. Biochim Biophys Acta 1763(12):1721–1732. doi:10.1016/j.bbamcr.2006.07.010

    Article  CAS  PubMed  Google Scholar 

  2. Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, Kass NE, Moser HW (2001) Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol 49(4):512–517

    Article  CAS  PubMed  Google Scholar 

  3. Dubois-Dalcq M, Feigenbaum V, Aubourg P (1999) The neurobiology of X-linked adrenoleukodystrophy: a demyelinating peroxisomal disorder. Trends Neurosci 22(1):4–12

    Article  CAS  PubMed  Google Scholar 

  4. Singh I, Pujol A (2010) Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol 20(4):838–844. doi:10.1111/j.1750-3639.2010.00392.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Moser HW, Loes DJ, Melhem ER, Raymond GV, Bezman L, Cox CS, Lu SE (2000) X-linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality: a study involving 372 patients. Neuropediatrics 31(5):227–239

    Article  CAS  PubMed  Google Scholar 

  6. Moser HW (1993) Lorenzo oil therapy for adrenoleukodystrophy: a prematurely amplified hope. Ann Neurol 34(2):121–122. doi:10.1002/ana.410340202

    Article  CAS  PubMed  Google Scholar 

  7. Contreras M, Sengupta TK, Sheikh F, Aubourg P, Singh I (1996) Topology of ATP-binding domain of adrenoleukodystrophy gene product in peroxisomes. Arch Biochem Biophys 334(2):369–379. doi:10.1006/abbi.1996.0467

    Article  CAS  PubMed  Google Scholar 

  8. Contreras M, Mosser J, Mandel JL, Aubourg P, Singh I (1994) The protein coded by the X-adrenoleukodystrophy gene is a peroxisomal integral membrane protein. FEBS Lett 344(2–3):211–215

    Article  CAS  PubMed  Google Scholar 

  9. Singh I, Moser AE, Goldfischer S, Moser HW (1984) Lignoceric acid is oxidized in the peroxisome: implications for the Zellweger cerebro-hepato-renal syndrome and adrenoleukodystrophy. Proc Natl Acad Sci U S A 81(13):4203–4207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shinnoh N, Yamada T, Yoshimura T, Furuya H, Yoshida Y, Suzuki Y, Shimozawa N, Orii T, Kobayashi T (1995) Adrenoleukodystrophy: the restoration of peroxisomal β-Oxidaton by transfection of normal cDNA. Biochem Biophys Res Commun 210(3):830–836. doi:10.1006/bbrc.1995.1733

    Article  CAS  PubMed  Google Scholar 

  11. Lombard-Platet G, Savary S, Sarde CO, Mandel JL, Chimini G (1996) A close relative of the adrenoleukodystrophy (ALD) gene codes for a peroxisomal protein with a specific expression pattern. Proc Natl Acad Sci U S A 93(3):1265–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Holzinger A, Kammerer S, Berger J, Roscher AA (1997) cDNA cloning and mRNA expression of the human adrenoleukodystrophy related protein (ALDRP), a peroxisomal ABC transporter. Biochem Biophys Res Commun 239(1):261–264. doi:10.1006/bbrc.1997.7391

    Article  CAS  PubMed  Google Scholar 

  13. Liu LX, Janvier K, Berteaux-Lecellier V, Cartier N, Benarous R, Aubourg P (1999) Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters. J Biol Chem 274(46):32738–32743

    Article  CAS  PubMed  Google Scholar 

  14. Tsuji S, Sano T, Ariga T, Miyatake T (1981) Increased synthesis of hexacosanoic acid (C23:0) by cultured skin fibroblasts from patients with adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN). J Biochem 90(4):1233–1236

    Article  CAS  PubMed  Google Scholar 

  15. Kemp S, Valianpour F, Denis S, Ofman R, Sanders RJ, Mooyer P, Barth PG, Wanders RJ (2005) Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy. Mol Genet Metab 84(2):144–151

    Article  CAS  PubMed  Google Scholar 

  16. Koike R, Tsuji S, Ohno T, Suzuki Y, Orii T, Miyatake T (1991) Physiological significance of fatty acid elongation system in adrenoleukodystrophy. J Neurol Sci 103(2):188–194

    Article  CAS  PubMed  Google Scholar 

  17. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Lee Y, Samaco RC, Gatchel JR, Thaller C, Orr HT, Zoghbi HY (2008) miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis. Nat Neurosci 11(10):1137–1139. doi:10.1038/nn.2183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL, Bassel-Duby R, Sanes JR, Olson EN (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326(5959):1549–1554. doi:10.1126/science.1181046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Miyazaki Y, Adachi H, Katsuno M, Minamiyama M, Jiang YM, Huang Z, Doi H, Matsumoto S, Kondo N, Iida M, Tohnai G, Tanaka F, Muramatsu S, Sobue G (2012) Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. Nat Med 18(7):1136–1141. doi:10.1038/nm.2791

    Article  CAS  PubMed  Google Scholar 

  25. Lu M, Zhang Q, Deng M, Miao J, Guo Y, Gao W, Cui Q (2008) An analysis of human microRNA and disease associations. PLoS One 3(10), e3420. doi:10.1371/journal.pone.0003420

    Article  PubMed  PubMed Central  Google Scholar 

  26. Baarine M, Khan M, Singh A, Singh I (2015) Functional characterization of IPSC-derived brain cells as a model for X-linked adrenoleukodystrophy. PLoS One 10(11), e0143238. doi:10.1371/journal.pone.0143238

    Article  PubMed  PubMed Central  Google Scholar 

  27. Singh J, Khan M, Pujol A, Baarine M, Singh I (2013) Histone deacetylase inhibitor upregulates peroxisomalfatty acid oxidation and inhibits apoptotic cell death inabcd1-deficient glial cells. PLoS One 8(7), e70712. doi:10.1371/journal.pone.0070712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Singh J, Khan M, Singh I (2009) Silencing of Abcd1 and Abcd2 genes sensitizes astrocytes for inflammation: implication for X-adrenoleukodystrophy. J Lipid Res 50(1):135–147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Baarine M, Beeson C, Singh A, Singh I (2014) ABCD1 deletion-induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy. J Neurochem. doi:10.1111/jnc.12992

    Google Scholar 

  30. Moser AB, Kreiter N, Bezman L, Lu S, Raymond GV, Naidu S, Moser HW (1999) Plasma very long chain fatty acids in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 45(1):100–110

    Article  CAS  PubMed  Google Scholar 

  31. Ofman R, Dijkstra IM, van Roermund CW, Burger N, Turkenburg M, van Cruchten A, van Engen CE, Wanders RJ, Kemp S (2010) The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy. EMBO Mol Med 2(3):90–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978. doi:10.1093/emboj/20.24.6969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Khan M, Singh J, Gilg A, Uto T, Singh I (2010) Very long-chain fatty acid accumulation causes lipotoxic response via 5-lipoxygenase in cerebral adrenoleukodystrophy. J Lipid Res 51(7):1685–1695. doi:10.1194/jlr.M002329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267(5203):1485–1488

    Article  CAS  PubMed  Google Scholar 

  35. Finco T, Beg A, Baldwin AJ (1994) Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. Proc Natl Acad Sci U S A 91(25):11884–11888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tvrdik P, Westerberg R, Silve S, Asadi A, Jakobsson A, Cannon B, Loison G, Jacobsson A (2000) Role of a new mammalian gene family in the biosynthesis of very long chain fatty acids and sphingolipids. J Cell Biol 149(3):707–717

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Singh J, Khan M, Singh I (2011) HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes. J Lipid Res 52(11):2056–2069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shafi G, Aliya N, Munshi A (2010) MicroRNA signatures in neurological disorders. Can J Neurol Sci 37(2):177–185

    Article  PubMed  Google Scholar 

  39. Su W, Aloi MS, Garden GA (2016) MicroRNAs mediating CNS inflammation: small regulators with powerful potential. Brain Behav Immun 52:1–8. doi:10.1016/j.bbi.2015.07.003

    Article  PubMed  Google Scholar 

  40. Moser HW, Loes DJ, Melhem ER, Raymond GV, Bezman L, Cox CS, Lu SE (2000) X-Linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics 31(5):227–39. doi:10.1055/s-2000-9236

    Article  CAS  PubMed  Google Scholar 

  41. Sutovsky S, Kolnikova M, Petrovic R, Kollar B, Siarnik P, Chandoga J, Fischerova M, Turcani P (2014) Differing clinical presentations of two unrelated cases of X-linked adrenoleukodystrophy with identical mutation Y296C in the ABCD1 gene. Neuro Endocrinol Lett 35(5):411–416

    PubMed  Google Scholar 

  42. Moser HW (2006) Therapy of X-linked adrenoleukodystrophy. NeuroRx 3(2):246–253. doi:10.1016/j.nurx.2006.01.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Powers JM, Moser HW (1998) Peroxisomal disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis. Brain Pathol 8(1):101–120

    Article  CAS  PubMed  Google Scholar 

  44. Gilg AG, Singh AK, Singh I (2000) Inducible nitric oxide synthase in the central nervous system of patients with X-adrenoleukodystrophy. J Neuropathol Exp Neurol 59(12):1063–1069

    Article  CAS  PubMed  Google Scholar 

  45. Powers JM, Pei Z, Heinzer AK, Deering R, Moser AB, Moser HW, Watkins PA, Smith KD (2005) Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol 64(12):1067–1079

    Article  CAS  PubMed  Google Scholar 

  46. Sato F, Tsuchiya S, Meltzer SJ, Shimizu K (2011) MicroRNAs and epigenetics. FEBS J 278(10):1598–1609. doi:10.1111/j.1742-4658.2011.08089.x

    Article  CAS  PubMed  Google Scholar 

  47. Thomson DW, Bracken CP, Goodall GJ (2011) Experimental strategies for microRNA target identification. Nucleic Acids Res 39(16):6845–6853. doi:10.1093/nar/gkr330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Packer A, Xing Y, Harper S, Jones L, Davidson B (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gaughwin P, Ciesla M, Lahiri N, Tabrizi S, Brundin P, Björkqvist 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

    Article  CAS  PubMed  Google Scholar 

  50. Cheng PH, Li CL, Chang YF, Tsai SJ, Lai YY, Chan AW, Chen CM, Yang SH (2013) miR-196a ameliorates phenotypes of Huntington disease in cell, transgenic mouse, and induced pluripotent stem cell models. Am J Hum Genet 93(2):306–312. doi:10.1016/j.ajhg.2013.05.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu B, Xiang Y, Zhang H (2015) Circulating microRNA-196a as a candidate diagnostic biomarker for chronic hepatitis C. Mol Med Rep 12(1):105–110. doi:10.3892/mmr.2015.3386

    PubMed  PubMed Central  Google Scholar 

  52. Hou W, Tian Q, Zheng J, Bonkovsky HL (2010) MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. Hepatology 51(5):1494–1504. doi:10.1002/hep.23401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Makino T, Jinnin M, Etoh M, Yamane K, Kajihara I, Makino K, Ichihara A, Igata T, Sakai K, Fukushima S, Ihn H (2014) Down-regulation of microRNA-196a in the sera and involved skin of localized scleroderma patients. Eur J Dermatol: EJD 24(4):470–476. doi:10.1684/ejd.2014.2384

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Drs Baarine Mauhammad, Je-Seong Won, and Mushfiquddin Khan for helpful discussion. We thank Dr Avtar K. Singh for brain sectioning. We also thank Dr Nishant Saxena and Ms Danielle Lowe for the help in figure formatting and Ms Joyce Bryan for procurement of chemicals. These studies were supported by grants (NS22576 and NS37766) from the National Institutes of Health, Bethesda, MD. This work was also supported by the National Institutes of Health Grants C06 RR018823 and C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.

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  1. Department of Pediatrics, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC, USA

    Navjot Shah & Inderjit Singh

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Shah, N., Singh, I. MicroRNA Profiling Identifies miR-196a as Differentially Expressed in Childhood Adrenoleukodystrophy and Adult Adrenomyeloneuropathy. Mol Neurobiol 54, 1392–1403 (2017). https://doi.org/10.1007/s12035-016-9746-0

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