Skip to main content
SpringerLink
Log in

Epigenetic Landscape of Parkinson’s Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

  • Review
  • Published:
Neurotherapeutics

Abstract

Parkinson’s disease (PD) is a complex multifactorial disorder marked by extensive system-wide pathology, including a substantial loss of nigrostriatal dopaminergic neurons. The etiology of PD remains elusive, but there is considerable evidence that, in addition to well-defined genetic mechanisms environmental factors play a crucial role in disease pathogenesis. How the environment might influence the genetic factors and contribute to disease development and progression remains unclear. In recent years, epigenetic mechanisms such as DNA methylation, chromatin remodeling and alterations in gene expression via non-coding RNAs have begun to be revealed as potential factors in PD pathogenesis. Epigenetic modulation exists throughout life, beginning in prenatal stages, is dependent on the lifestyle, environmental exposure and genetic makeup of an individual and may serve as a missing link between PD risk factors and development of the disease. This chapter sheds light on the emerging role of epigenetics in disease pathogenesis and on prospective interventional strategies for the therapeutic modulation of PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Dorsey ER, Constantinescu R, Thompson JP, Biglan KM, Holloway RG, Kieburtz K, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384–6.

    Article  PubMed  CAS  Google Scholar 

  2. Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol. 1996;55(3):259–72.

    Article  PubMed  CAS  Google Scholar 

  3. Jablonka E, Lamb MJ. The changing concept of epigenetics. Ann NY Acad Sci. 2002;981:82–96.

    Article  PubMed  Google Scholar 

  4. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–68.

    Article  PubMed  CAS  Google Scholar 

  5. Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–8.

    Article  PubMed  CAS  Google Scholar 

  6. Jiang C, Pugh BF. Nucleosome positioning and gene regulation: advances through genomics. Nat Rev Genet. 2009;10(3):161–72.

    Article  PubMed  CAS  Google Scholar 

  7. Bergman Y, Cedar H. DNA methylation dynamics in health and disease. Nat Struct Mol Biol. 2013;20(3):274–81.

    Article  PubMed  CAS  Google Scholar 

  8. Orphanides G, Reinberg D. A unified theory of gene expression. Cell. 2002;108(4):439–51.

    Article  PubMed  CAS  Google Scholar 

  9. Watanabe Y, Maekawa M. Methylation of DNA in cancer. Adv Clin Chem. 2010;52:145–67.

    Article  PubMed  CAS  Google Scholar 

  10. Kinney SR, Pradhan S. Regulation of expression and activity of DNA (cytosine-5) methyltransferases in mammalian cells. Prog Mol Biol Transl Sci. 2011;101:311–33.

    Article  PubMed  CAS  Google Scholar 

  11. Luger K. Structure and dynamic behavior of nucleosomes. Curr Opin Genet Dev. 2003;13(2):127–35.

    Article  PubMed  CAS  Google Scholar 

  12. Marmorstein R, Roth SY. Histone acetyltransferases: function, structure, and catalysis. Curr Opin Genet Dev. 2001;11(2):155–61.

    Article  PubMed  CAS  Google Scholar 

  13. Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5(10):981–9.

    Article  PubMed  CAS  Google Scholar 

  14. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature. 2009;459(7243):55–60.

    Article  PubMed  CAS  Google Scholar 

  15. MacDonald JL, Roskams AJ. Histone deacetylases 1 and 2 are expressed at distinct stages of neuro-glial development. Dev Dyn. 2008;237(8):2256–67.

    Article  PubMed  Google Scholar 

  16. Habibi E, Masoudi-Nejad A, Abdolmaleky HM, Haggarty SJ. Emerging roles of epigenetic mechanisms in Parkinson’s disease. Funct Integr Genomics. 2011;11(4):523–37.

    Article  PubMed  CAS  Google Scholar 

  17. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.

    Article  PubMed  CAS  Google Scholar 

  18. Houlden H, Singleton AB. The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol. 2012;124(3):325–38.

    Article  PubMed  CAS  Google Scholar 

  19. Thomas B, Beal MF. Molecular insights into Parkinson’s disease. F1000 Med Rep. 2011;3:7.

    Google Scholar 

  20. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet. 2009;41(12):1303–7.

    Article  PubMed  CAS  Google Scholar 

  21. Cookson MR. alpha-Synuclein and neuronal cell death. Mol Neurodegener. 2009;4:9.

    Google Scholar 

  22. Kontopoulos E, Parvin JD, Feany MB. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Human molecular genetics. 2006;15(20):3012–23.

    Article  PubMed  CAS  Google Scholar 

  23. Jowaed A, Schmitt I, Kaut O, Wullner U. Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci. 2010;30(18):6355–9.

    Article  PubMed  CAS  Google Scholar 

  24. Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, et al. CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson’s disease. PLoS One. 2010;5(11):e15522.

    Article  PubMed  Google Scholar 

  25. Desplats P, Spencer B, Coffee E, Patel P, Michael S, Patrick C, et al. Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J Biol Chem. 2011;286(11):9031–7.

    Article  PubMed  CAS  Google Scholar 

  26. A two-stage meta-analysis identifies several new loci for Parkinson’s disease. PLoS genetics. 2011;7(6):e1002142.

  27. Bonsch D, Lenz B, Kornhuber J, Bleich S. DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism. Neuroreport. 2005;16(2):167–70.

    Article  PubMed  Google Scholar 

  28. Frieling H, Gozner A, Romer KD, Lenz B, Bonsch D, Wilhelm J, et al. Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry. 2007;12(3):229–30.

    Article  PubMed  CAS  Google Scholar 

  29. de Boni L, Tierling S, Roeber S, Walter J, Giese A, Kretzschmar HA. Next-generation sequencing reveals regional differences of the alpha-synuclein methylation state independent of Lewy body disease. Neuromolecular Med. 2011;13(4):310–20.

    Article  PubMed  CAS  Google Scholar 

  30. Voutsinas GE, Stavrou EF, Karousos G, Dasoula A, Papachatzopoulou A, Syrrou M, et al. Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease. Hum Mutat. 2010;31(6):685–91.

    Article  PubMed  CAS  Google Scholar 

  31. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science. 2007;317(5837):516–9.

    Article  PubMed  CAS  Google Scholar 

  32. St Laurent R, O’Brien LM, Ahmad ST. Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson’s disease. Neuroscience. 2013;246:382–90.

    Article  PubMed  CAS  Google Scholar 

  33. Siddiqui A, Chinta SJ, Mallajosyula JK, Rajagopolan S, Hanson I, Rane A, et al. Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson’s disease. Free Radical Biol Med. 2012;53(4):993–1003.

    Article  CAS  Google Scholar 

  34. Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, et al. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci TransMed. 2010;2(52):52ra73.

    Article  Google Scholar 

  35. Kirilyuk A, Shimoji M, Catania J, Sahu G, Pattabiraman N, Giordano A, et al. An intrinsically disordered region of the acetyltransferase p300 with similarity to prion-like domains plays a role in aggregation. PLoS One. 2012;7(11):e48243.

    Article  PubMed  CAS  Google Scholar 

  36. Jin H, Kanthasamy A, Ghosh A, Yang Y, Anantharam V, Kanthasamy AG. alpha-Synuclein negatively regulates protein kinase Cdelta expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. J Neurosci. 2011;31(6):2035–51.

    Article  PubMed  CAS  Google Scholar 

  37. Wang G, van der Walt JM, Mayhew G, Li YJ, Zuchner S, Scott WK, et al. Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. Am J Hum Genet. 2008;82(2):283–9.

    Article  PubMed  CAS  Google Scholar 

  38. Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM. Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci USA. 2009;106(31):13052–7.

    Article  PubMed  CAS  Google Scholar 

  39. Doxakis E. Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J Biol Chem. 2010;285(17):12726–34.

    Article  PubMed  CAS  Google Scholar 

  40. Gillardon F, Mack M, Rist W, Schnack C, Lenter M, Hildebrandt T, et al. MicroRNA and proteome expression profiling in early-symptomatic alpha-synuclein(A30P)-transgenic mice. Proteomics Clin Appl. 2008;2(5):697–705.

    Article  PubMed  CAS  Google Scholar 

  41. Asikainen S, Rudgalvyte M, Heikkinen L, Louhiranta K, Lakso M, Wong G, et al. Global microRNA expression profiling of Caenorhabditis elegans Parkinson’s disease models. J Mol Neurosci. 2010;41(1):210–8.

    Article  PubMed  CAS  Google Scholar 

  42. Cho HJ, Liu G, Jin SM, Parisiadou L, Xie C, Yu J, et al. MicroRNA-205 regulates the expression of Parkinson’s disease-related leucine-rich repeat kinase 2 protein. Human molecular genetics. 2013;22(3):608–20.

    Article  PubMed  CAS  Google Scholar 

  43. Gehrke S, Imai Y, Sokol N, Lu B. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature. 2010;466(7306):637–41.

    Article  PubMed  CAS  Google Scholar 

  44. Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci. 2006;9(10):1231–3.

    Article  PubMed  CAS  Google Scholar 

  45. Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, et al. Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 2008;27(18):2432–43.

    Article  PubMed  CAS  Google Scholar 

  46. Agirre X, Roman-Gomez J, Vazquez I, Jimenez-Velasco A, Garate L, Montiel-Duarte C, et al. Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia. Int J Cancer. 2006;118(8):1945–53.

    Article  PubMed  CAS  Google Scholar 

  47. Cai M, Tian J, Zhao GH, Luo W, Zhang BR. Study of methylation levels of parkin gene promoter in Parkinson’s disease patients. Int J Neurosci. 2011;121(9):497–502.

    Article  PubMed  CAS  Google Scholar 

  48. Barrachina M, Ferrer I. DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. J Neuropathol Exp Neurol. 2009;68(8):880–91.

    Article  PubMed  CAS  Google Scholar 

  49. Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S, et al. Distinct DNA methylation changes highly correlated with chronological age in the human brain. Human Molec Genet. 2011;20(6):1164–72.

    Article  CAS  Google Scholar 

  50. Hardison RC. Genome-wide epigenetic data facilitate understanding of disease susceptibility association studies. J Biol Chem. 2012;287(37):30932–40.

    Article  PubMed  CAS  Google Scholar 

  51. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5(6):525–35.

    Article  PubMed  Google Scholar 

  52. Blandini F, Fancellu R, Martignoni E, Mangiagalli A, Pacchetti C, Samuele A, et al. Plasma homocysteine and l-dopa metabolism in patients with Parkinson disease. Clin Chem. 2001;47(6):1102–4.

    PubMed  CAS  Google Scholar 

  53. Obeid R, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W. Methylation status and neurodegenerative markers in Parkinson disease. Clin Chem. 2009;55(10):1852–60.

    Article  PubMed  CAS  Google Scholar 

  54. Maeda T, Guan JZ, Oyama J, Higuchi Y, Makino N. Aging-associated alteration of subtelomeric methylation in Parkinson’s disease. J Gerontol A Biol Sci Med Sci. 2009;64(9):949–55.

    Article  PubMed  Google Scholar 

  55. Margis R, Margis R, Rieder CR. Identification of blood microRNAs associated to Parkinsonis disease. J Biotechnol. 2011;152(3):96–101.

    Article  PubMed  CAS  Google Scholar 

  56. Minones-Moyano E, Porta S, Escaramis G, Rabionet R, Iraola S, Kagerbauer B, et al. MicroRNA profiling of Parkinson’s disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Human Molec Genet. 2011;20(15):3067–78.

    Article  CAS  Google Scholar 

  57. Kopin IJ. Toxins and Parkinson’s disease: MPTP parkinsonism in humans and animals. Adv Neurol. 1987;45:137–44.

    PubMed  CAS  Google Scholar 

  58. Fukuda T. Neurotoxicity of MPTP. Neuropathology. 2001;21(4):323–32.

    Article  PubMed  CAS  Google Scholar 

  59. Van Maele-Fabry G, Hoet P, Vilain F, Lison D. Occupational exposure to pesticides and Parkinson’s disease: a systematic review and meta-analysis of cohort studies. Environ Int. 2012;46:30–43.

    Article  PubMed  Google Scholar 

  60. Zaheer F, Slevin JT. Trichloroethylene and Parkinson disease. Neurol Clin. 2011;29(3):657–65.

    Article  PubMed  Google Scholar 

  61. Franco R, Li S, Rodriguez-Rocha H, Burns M, Panayiotidis MI. Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson’s disease. Chem Biol Interact. 2010;188(2):289–300.

    Article  PubMed  CAS  Google Scholar 

  62. Kanthasamy A, Jin H, Anantharam V, Sondarva G, Rangasamy V, Rana A, et al. Emerging neurotoxic mechanisms in environmental factors-induced neurodegeneration. Neurotoxicology. 2012;33(4):833–7.

    Article  PubMed  Google Scholar 

  63. Song C, Kanthasamy A, Anantharam V, Sun F, Kanthasamy AG. Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. Mol Pharmacol. 2010;77(4):621–32.

    Article  PubMed  CAS  Google Scholar 

  64. Song C, Kanthasamy A, Jin H, Anantharam V, Kanthasamy AG. Paraquat induces epigenetic changes by promoting histone acetylation in cell culture models of dopaminergic degeneration. Neurotoxicology. 2011;32(5):586–95.

    Article  PubMed  CAS  Google Scholar 

  65. Nicholas AP, Lubin FD, Hallett PJ, Vattem P, Ravenscroft P, Bezard E, et al. Striatal histone modifications in models of levodopa-induced dyskinesia. J Neurochem. 2008;106(1):486–94.

    Article  PubMed  CAS  Google Scholar 

  66. Thomas B, Mandir AS, West N, Liu Y, Andrabi SA, Stirling W, et al. Resistance to MPTP-neurotoxicity in alpha-synuclein knockout mice is complemented by human alpha-synuclein and associated with increased beta-synuclein and Akt activation. PLoS One. 2011;6(1):e16706.

    Article  PubMed  CAS  Google Scholar 

  67. Xu Z, Li H, Jin P. Epigenetics-based therapeutics for neurodegenerative disorders. Curr Transl Geriatr Exp Gerontol Rep. 2012;1(4):229–36.

    Article  PubMed  CAS  Google Scholar 

  68. Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS, Thompson LM, et al. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Human Molec Genet. 2008;17(23):3767–75.

    Article  CAS  Google Scholar 

  69. Darmopil S, Martin AB, De Diego IR, Ares S, Moratalla R. Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation. Biol Psychiatry. 2009;66(6):603–13.

    Article  PubMed  CAS  Google Scholar 

  70. Kidd SK, Schneider JS. Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neuroscience. 2011;194:189–94.

    Article  PubMed  CAS  Google Scholar 

  71. Chen PS, Wang CC, Bortner CD, Peng GS, Wu X, Pang H, et al. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience. 2007;149(1):203–12.

    Article  PubMed  CAS  Google Scholar 

  72. Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, et al. Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Brain Res Mol Brain Res. 2005;134(1):162–9.

    Article  PubMed  CAS  Google Scholar 

  73. Marinova Z, Ren M, Wendland JR, Leng Y, Liang MH, Yasuda S, et al. Valproic acid induces functional heat-shock protein 70 via class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation. J Neurochem. 2009;111(4):976–87.

    Article  PubMed  CAS  Google Scholar 

  74. Kidd SK, Schneider JS. Protection of dopaminergic cells from MPP + −mediated toxicity by histone deacetylase inhibition. Brain Res. 2010;1354:172–8.

    Article  PubMed  CAS  Google Scholar 

  75. Chen H, Dzitoyeva S, Manev H. Effect of valproic acid on mitochondrial epigenetics. Eur J Pharmacol. 2012;690(1–3):51–9.

    Article  PubMed  CAS  Google Scholar 

  76. Wu X, Chen PS, Dallas S, Wilson B, Block ML, Wang CC, et al. Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J Neuropsychopharmacol. 2008;11(8):1123–34.

    Article  PubMed  CAS  Google Scholar 

  77. Marinova Z, Leng Y, Leeds P, Chuang DM. Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons. Neuropharmacology. 2011;60(7–8):1109–15.

    Article  PubMed  CAS  Google Scholar 

  78. Leng Y, Marinova Z, Reis-Fernandes MA, Nau H, Chuang DM. Potent neuroprotective effects of novel structural derivatives of valproic acid: potential roles of HDAC inhibition and HSP70 induction. Neurosci Lett. 2010;476(3):127–32.

    Article  PubMed  CAS  Google Scholar 

  79. Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem. 2011;286(17):14941–51.

    Article  PubMed  CAS  Google Scholar 

  80. Roy A, Ghosh A, Jana A, Liu X, Brahmachari S, Gendelman HE, et al. Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson’s disease. PLoS One. 2012;7(6):e38113.

    Article  PubMed  CAS  Google Scholar 

  81. Huang HY, Lin SZ, Chen WF, Li KW, Kuo JS, Wang MJ. Urocortin modulates dopaminergic neuronal survival via inhibition of glycogen synthase kinase-3beta and histone deacetylase. Neurobiol Aging. 2011;32(9):1662–77.

    Article  PubMed  CAS  Google Scholar 

  82. Moving AHEAD with an international human epigenome project. Nature. 2008;454(7205):711–5.

Download references

Acknowledgments

N.A.K is a Parkinson’s Disease Foundation fellow. This work was supported in part by grants from the National Institutes of Health (grant #NS060885), the Michael J Fox Foundation for Parkinson’s disease, and STARTUP funds from the Medical College of Georgia to B.T.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912, Augusta, Georgia

    Navneet Ammal Kaidery, Shaista Tarannum & Bobby Thomas

  2. Department of Neurology, Medical College of Georgia, Georgia Regents University, 1459 Laney Walker Blvd, CB-3618, 30912, Augusta, Georgia

    Bobby Thomas

Authors
  1. Navneet Ammal Kaidery
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaista Tarannum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bobby Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bobby Thomas.

Additional information

Navneet Ammal Kaidery and Shaista Tarannum contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 498 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ammal Kaidery, N., Tarannum, S. & Thomas, B. Epigenetic Landscape of Parkinson’s Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities. Neurotherapeutics 10, 698–708 (2013). https://doi.org/10.1007/s13311-013-0211-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13311-013-0211-8

Keywords

Search

Navigation