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Whole-Transcriptome Analysis of Dermal Fibroblasts, Derived from Three Pairs of Monozygotic Twins, Discordant for Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. In most cases, the development of the disease is sporadic and is not associated with any currently known mutations associated with PD. It is believed that changes associated with the epigenetic regulation of gene expression may play an important role in the pathogenesis of this disease. The study of individuals with an almost identical genetic background, such as monozygotic twins, is one of the best approaches to the analysis of such changes. A whole-transcriptome analysis of dermal fibroblasts obtained from three pairs of monozygotic twins discordant for PD was carried out in this work. Twenty-nine differentially expressed genes were identified in the three pairs of twins. These genes were included in seven processes within two clusters, according to the results of an enrichment analysis. The cluster with the greatest statistical significance included processes associated with the regulation of the differentiation of fat cells, the action potential, and the regulation of glutamatergic synaptic transmission. The most significant genes, which occupied a central position in this cluster, were PTGS2, SCN9A, and GRIK2. These genes can be considered as potential candidate genes for PD.

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Abbreviations

PD:

Parkinson’s disease

DAergic:

Dopaminergic

FBS:

Fetal bovine serum

DEGs:

Differentially expressed genes

References

  1. Bindea G et al (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093. https://doi.org/10.1093/bioinformatics/btp101

  2. Bindea G, Galon J, Mlecnik B (2013) CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data. Bioinformatics 29:661–663. https://doi.org/10.1093/bioinformatics/btt019

  3. Castillo PE, Malenka RC, Nicoll RA (1997) Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388:182–186. https://doi.org/10.1038/40645

  4. Contractor A, Swanson GT, Sailer A, O'Gorman S, Heinemann SF (2000) Identification of the kainate receptor subunits underlying modulation of excitatory synaptic transmission in the CA3 region of the hippocampus. J Neurosci 20:8269–8278

  5. Cookson MR, Hardy J, Lewis PA (2008) Genetic neuropathology of Parkinson’s disease. Int J Clin Exp Pathol 1:217–231

  6. Cox JJ et al (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894–898. https://doi.org/10.1038/nature05413

  7. Crabtree GR, Olson EN (2002) NFAT signaling: choreographing the social lives of cells. Cell 109(Suppl):S67–S79. https://doi.org/10.1016/s0092-8674(02)00699-2

  8. Cregg R, Momin A, Rugiero F, Wood JN, Zhao J (2010) Pain channelopathies. J Physiol 588:1897–1904. https://doi.org/10.1113/jphysiol.2010.187807

  9. Dobin A et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. https://doi.org/10.1093/bioinformatics/bts635

  10. Fahn BS, Elton R, M.o.t.U.D. Committee (1987) Unified Parkinson’s disease rating scale. Recent developments in Parkinson’s disease. Macmillan Health Care Information, Florham Park

  11. Fisahn A, Contractor A, Traub RD, Buhl EH, Heinemann SF, McBain CJ (2004) Distinct roles for the kainate receptor subunits GluR5 and GluR6 in kainate-induced hippocampal gamma oscillations. J Neurosci 24:9658–9668. https://doi.org/10.1523/JNEUROSCI.2973-04.2004

  12. Gasser T (2009) Molecular pathogenesis of Parkinson disease: insights from genetic studies. Expert Rev Mol Med 11:e22. https://doi.org/10.1017/S1462399409001148S1462399409001148

  13. Goetz CG et al (2004) Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19:1020–1028. https://doi.org/10.1002/mds.20213

  14. Graef IA, Wang F, Charron F, Chen L, Neilson J, Tessier-Lavigne M, Crabtree GR (2003) Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113:657–670. https://doi.org/10.1016/s0092-8674(03)00390-8

  15. Hawkes CH, Shephard BC, Daniel SE (1997) Olfactory dysfunction in Parkinson’s disease. J Neuronal Neurosurg Psychiat 62:436–446

  16. Hettne KM et al (2016) The implicitome: a resource for rationalizing gene-disease associations. PLoS One 11:e0149621. https://doi.org/10.1371/journal.pone.0149621

  17. Hoffmann T et al (2018) NaV1.7 and pain: contribution of peripheral nerves. Pain 159:496–506. https://doi.org/10.1097/j.pain.0000000000001119

  18. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184

  19. Kalia LV, Lang AE (2015) Parkinson's disease. Lancet 386:896–912. https://doi.org/10.1016/S0140-6736(14)61393-3

  20. Kalinderi K, Bostantjopoulou S, Fidani L (2016) The genetic background of Parkinson's disease: current progress and future prospects. Acta Neurol Scand 134:314–326. https://doi.org/10.1111/ane.12563

  21. Kaufmann WE, Andreasson KI, Isakson PC, Worley PF (1997) Cyclooxygenases and the central nervous system. Prostaglandins 54:601–624

  22. Kaut O et al (2017) Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic patterns in peripheral blood mononuclear cells. Neurogenetics 18:7–22. https://doi.org/10.1007/s10048-016-0497-x

  23. Klee CB, Crouch TH, Krinks MH (1979) Calcineurin: a calcium- and calmodulin-binding protein of the nervous system. Proc Natl Acad Sci U S A 76:6270–6273. https://doi.org/10.1073/pnas.76.12.6270

  24. Kullmann DM (2001) Presynaptic kainate receptors in the hippocampus: slowly emerging from obscurity. Neuron 32:561–564

  25. Lauri SE, Delany C, J Clarke VR, Bortolotto ZA, Ornstein PL, Isaac J TR, Collingridge GL (2001) Synaptic activation of a presynaptic kainate receptor facilitates AMPA receptor-mediated synaptic transmission at hippocampal mossy fibre synapses. Neuropharmacology 41:907–915

  26. Lesage S, Brice A (2009) Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 18:R48–R59. https://doi.org/10.1093/hmg/ddp012

  27. Lesage S, Brice A (2012) Role of mendelian genes in "sporadic" Parkinson's disease. Parkinsonism Relat Disord 18(Suppl 1):S66–S70. https://doi.org/10.1016/S1353-8020(11)70022-0

  28. Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12:323. https://doi.org/10.1186/1471-2105-12-323

  29. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif) 25:402–408. https://doi.org/10.1006/meth.2001.1262

  30. Luo J et al (2014) A calcineurin- and NFAT-dependent pathway is involved in alpha-synuclein-induced degeneration of midbrain dopaminergic neurons. Hum Mol Genet 23:6567–6574. https://doi.org/10.1093/hmg/ddu377

  31. Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5:472–484. https://doi.org/10.1038/nri1632

  32. Maraschi A et al (2014) Parkin regulates kainate receptors by interacting with the GluK2 subunit. Nat Commun 5:5182. https://doi.org/10.1038/ncomms6182

  33. Minghetti L (2004) Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropathol Exp Neurol 63:901–910. https://doi.org/10.1093/jnen/63.9.901

  34. Muller A, Mungersdorf M, Reichmann H, Strehle G, Hummel T (2002) Olfactory function in Parkinsonian syndromes. J Clin Neurosci 9:521–524

  35. Nguyen T, Di Giovanni S (2008) NFAT signaling in neural development and axon growth. Int J Dev Neurosci 26:141–145. https://doi.org/10.1016/j.ijdevneu.2007.10.004

  36. Niranjan R, Mishra KP, Thakur AK (2018) Inhibition of cyclooxygenase-2 (COX-2) initiates autophagy and potentiates MPTP-induced autophagic cell death of human neuroblastoma cells, SH-SY5Y: an inside in the pathology of Parkinson's disease. Mol Neurobiol 55:8038–8050. https://doi.org/10.1007/s12035-018-0950-y

  37. Planken A, Kurvits L, Reimann E, Kadastik-Eerme L, Kingo K, Koks S, Taba P (2017) Looking beyond the brain to improve the pathogenic understanding of Parkinson's disease: implications of whole transcriptome profiling of Patients' skin. BMC Neurol 17:6. https://doi.org/10.1186/s12883-016-0784-z

  38. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47. https://doi.org/10.1093/nar/gkv007

  39. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140. https://doi.org/10.1093/bioinformatics/btp616

  40. Schubert M, Lindgreen S, Orlando L (2016) AdapterRemoval v2: rapid adapter trimming, identification, and read merging. BMC Res Notes 9:88. https://doi.org/10.1186/s13104-016-1900-2

  41. Schwartz N, Schohl A, Ruthazer ES (2009) Neural activity regulates synaptic properties and dendritic structure in vivo through calcineurin/NFAT signaling. Neuron 62:655–669. https://doi.org/10.1016/j.neuron.2009.05.007

  42. Shewchuk BM (2014) Prostaglandins and n-3 polyunsaturated fatty acids in the regulation of the hypothalamic-pituitary axis. Prostaglandins Leukot Essent Fat Acids 91:277–287. https://doi.org/10.1016/j.plefa.2014.09.005

  43. Singleton AB, Farrer MJ, Bonifati V (2013) The genetics of Parkinson's disease: progress and therapeutic implications. Mov Disord 28:14–23. https://doi.org/10.1002/mds.25249

  44. Soto-Ortolaza AI, Ross OA (2016) Genetic susceptibility variants in parkinsonism. Parkinsonism Relat Disord 22(Suppl 1):S7–S11. https://doi.org/10.1016/j.parkreldis.2015.09.011

  45. Suslov O, Steindler DA (2005) PCR inhibition by reverse transcriptase leads to an overestimation of amplification efficiency. Nucleic Acids Res 33:e181. https://doi.org/10.1093/nar/gni176

  46. Swanson GT, Sakai R (2009) Ligands for ionotropic glutamate receptors. Prog Mol Subcell Biol 46:123–157. https://doi.org/10.1007/978-3-540-87895-7_5

  47. Teismann P et al (2003) Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc Natl Acad Sci U S A 100:5473–5478. https://doi.org/10.1073/pnas.0837397100

  48. The Gene Ontology C (2019) The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res 47:D330–D338. https://doi.org/10.1093/nar/gky1055

  49. Verkhratsky A, Kirchhoff F (2007) Glutamate-mediated neuronal-glial transmission. J Anat 210:651–660. https://doi.org/10.1111/j.1469-7580.2007.00734.x

  50. Weiss J et al (2011) Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 472:186–190. https://doi.org/10.1038/nature09975

  51. Wheeler DL et al. (2003) Database resources of the National Center for Biotechnology Nucleic Acids Res 31:28-33 https://doi.org/10.1093/nar/gkg033

  52. Woodard CM et al (2014) iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson's disease. Cell Rep 9:1173–1182. https://doi.org/10.1016/j.celrep.2014.10.023

  53. Wu L, Wang Q, Liang X, Andreasson K (2007) Divergent effects of prostaglandin receptor signaling on neuronal survival. Neurosci Lett 421:253–258. https://doi.org/10.1016/j.neulet.2007.05.055

  54. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11:371–386

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Acknowledgments

The work was carried out using equipment of the Center of Cellular and Gene Technology of the Institute of Molecular Genetics of the Russian Academy of Sciences.

Funding

This work was supported by the Russian Foundation for Basic Research (project no. 18-315-20009).

Author information

Correspondence to Margarita M. Rudenok.

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Competing Interests

The authors declare that they have no competing interests.

Statement of Informed Consent

Written informed consent for the use of biological material was obtained from all study participants.

The study was conducted in accordance with the World Medical Assembly Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. This work was approved by the Ethics Committee of the Institute of Molecular Genetics of Russian Academy of Sciences.

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Highlights

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases.

A highly rare phenomenon is described: i.e., monozygotic twins discordant for PD.

Processes directly related with the functioning of the nervous system were revealed.

PTGS2, SCN9A, and GRIK2 can be considered as potential candidate genes for PD.

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Alieva, A.K., Rudenok, M.M., Novosadova, E.V. et al. Whole-Transcriptome Analysis of Dermal Fibroblasts, Derived from Three Pairs of Monozygotic Twins, Discordant for Parkinson’s Disease. J Mol Neurosci 70, 284–293 (2020). https://doi.org/10.1007/s12031-019-01452-3

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Keywords

  • Parkinson’s disease
  • Whole-transcriptome analysis
  • Twins
  • Fibroblasts
  • Gene expression