Advertisement

Neurotrophic Support of Midbrain Dopaminergic Neurons

  • Oliver von BohlenEmail author
  • Klaus Unsicker
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 651)

Abstract

In this chapter we review work on neurotrophic factors for midbrain dopaminergic neurons mainly from the past decade, with a focus on neurotrophins and fibroblast growth factors. We summarize data obtained from animal models of Parkinson’s disease, review analyses of neurotrophin, neurotrophin receptor and FGF-2 knockout mice and put these into context with data obtained from patients with Parkinson’s disease and from postmortem studies. We provide a brief overview on several other factors (EGF, TGF-α, IGF, CNTF, PDGF, interleukins) and their capacity to promote survival and protect lesioned DAergic neurons. TGF-βs are reviewed in a separate chapter (Roussa et al, this volume).

Keywords

Substantia Nigra Dopaminergic Neuron Basic Fibroblast Growth Factor Neurotrophin Receptor BDNF mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Chase TN, Oh JD, Blanchet PJ. Neostriatal mechanisms in Parkinson’s disease. Neurology 1998; 51:S30–S35.PubMedGoogle Scholar
  2. 2.
    von Bohlen und Halbach O, Schober A, Krieglstein K. Genes, proteins and neurotoxins involved in Parkinson’s disease. Prog Neurobiol 2004; 73:151–177.CrossRefGoogle Scholar
  3. 3.
    Krieglstein K. Factors promoting survival of mesencephalic dopaminergic neurons. Cell Tissue Res 2004; 318:73–80.CrossRefPubMedGoogle Scholar
  4. 4.
    Unsicker K. Growth factors in Parkinson’s disease. Prog Growth Factor Res 1994; 5:73–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Nagatsu T, Mogi M, Ichinose H et al. Cytokines in Parkinson’s disease. J Neural Transm Suppl 2000; 143–151.Google Scholar
  6. 6.
    Reuss B, von Bohlen und Halbach O. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res 2003; 313:139–157.CrossRefPubMedGoogle Scholar
  7. 7.
    Barde YA. Neurotrophins: a family of proteins supporting the survival of neurons. Prog Clin Biol Res 1994; 390:45–56.PubMedGoogle Scholar
  8. 8.
    Frade JM, Barde YA. Nerve growth factor: two receptors, multiple functions. Bioessays 1998; 20:137–145.CrossRefPubMedGoogle Scholar
  9. 9.
    Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol 1994; 25:1386–1403.CrossRefPubMedGoogle Scholar
  10. 10.
    Chao MV. Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 2003; 4:299–309.CrossRefPubMedGoogle Scholar
  11. 11.
    Altar CA, Siuciak JA, Wright P et al. In situ hybridization of trkB and trkC receptor mRNA in rat forebrain and association with high-affinity binding of [125I]BDNF, [125I]NT-4/5 and [125I]NT-3. Eur J Neurosci 1994; 6:1389–1405.CrossRefPubMedGoogle Scholar
  12. 12.
    Katoh-Semba R, Semba R, Takeuchi IK et al. Age-related changes in levels of brain-derived neurotrophic factor in selected brain regions of rats, normal mice and senescence-accelerated mice: a comparison to those of nerve growth factor and neurotrophin-3. Neurosci Res 1998; 31:227–234.CrossRefPubMedGoogle Scholar
  13. 13.
    Nishio T, Furukawa S, Akiguchi I et al. Medial nigral dopamine neurons have rich neurotrophin support in humans. NeuroReport 1998; 9:2847–2851.PubMedGoogle Scholar
  14. 14.
    Numan S, Seroogy KB. Expression of trkB and trkC mRNAs by adult midbrain dopamine neurons: a double-label in situ hybridization study. J Comp Neurol 1999; 403:295–308.CrossRefPubMedGoogle Scholar
  15. 15.
    Hyman C, Hofer M, Barde YA et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350:230–232.CrossRefPubMedGoogle Scholar
  16. 16.
    Hagg T. Neurotrophins prevent death and differentially affect tyrosine hydroxylase of adult rat nigrostrialal neurons in vivo. Exp Neurol 1998; 149:183–192.CrossRefPubMedGoogle Scholar
  17. 17.
    Hynes MA, Poulsen K, Armanini M et al. Neurotrophin-4/5 is a survival factor for embryonic midbrain dopaminergic neurons in enriched cultures. J Neurosci Res 1994; 37:144–154.CrossRefPubMedGoogle Scholar
  18. 18.
    Hyman C, Juhasz M, Jackson C et al. Overlapping and distinct actions of the neurotrophins BDNF, NT-3 and NT-4/5 on cultured dopaminergic and GABAergic neurons of the ventral mesencephalon. J Neurosci 1994; 14:335–347.PubMedGoogle Scholar
  19. 19.
    Baquet ZC, Bickford PC, Jones KR. Brain-derived neurotrophic factor is required for the establishment of the proper number of dopaminergic neurons in the substantia nigra pars compacta. J Neurosci 2005; 25: 6251–6259.CrossRefPubMedGoogle Scholar
  20. 20.
    Venero JL, Beck KD, Hefti F. 6-Hydroxydopamine lesions reduce BDNF mRNA levels in adult rat brain substantia nigra. NeuroReport 1994; 5:429–432.CrossRefPubMedGoogle Scholar
  21. 21.
    Altar CA, Boylan CB, Fritsche M et al. Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions. J Neurochem 1994; 63:1021–1032.PubMedGoogle Scholar
  22. 22.
    Singh S, Ahmad R, Mathur D et al. Neuroprotective effect of BDNF in young and aged 6-OHDA treated rat model of Parkinson disease. Indian J Exp Biol 2006; 44:699–704.PubMedGoogle Scholar
  23. 23.
    Klein RL, Lewis MH, Muzyczka N et al. Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer. Brain Res 1999; 847:314–320.CrossRefPubMedGoogle Scholar
  24. 24.
    Levivier M, Przedborski S, Bencsics C et al. Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 1995; 15:7810–7820.PubMedGoogle Scholar
  25. 25.
    Frim DM, Uhler TA, Galpern WR et al. Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 1994; 91:5104–5108.CrossRefPubMedGoogle Scholar
  26. 26.
    Galpern WR, Frim DM, Tatter SB et al. Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration. Cell Transplant 1996; 5:225–232.CrossRefPubMedGoogle Scholar
  27. 27.
    Howells DW, Porritt MJ, Wong JY et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 2000; 166:127–135.CrossRefPubMedGoogle Scholar
  28. 28.
    Mogi M, Togari A, Kondo T et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett 1999; 270:45–48.CrossRefPubMedGoogle Scholar
  29. 29.
    Zaman V, Nelson ME, Gerhardt GA et al. Neurodegenerative alterations in the nigrostriatal system of trkB hypomorphic mice. Exp Neurol 2004; 190:337–346.CrossRefPubMedGoogle Scholar
  30. 30.
    von Bohlen und Halbach O, Minichiello L, Unsicker K. Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra. FASEB J 2005; 19:1740–1742.Google Scholar
  31. 31.
    Kramer ER, Aron L, Ramakers GM et al. Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System. PLoS Biol 2007; 5:e39.CrossRefPubMedGoogle Scholar
  32. 32.
    von Bohlen und Halbach O, Minichiello L. Neurotrophin receptor heterozygosity causes deficits in catecholaminergic innervation of amygdala and hippocampus in aged mice. J Neural Transm 2006; 113:1829–1836.CrossRefGoogle Scholar
  33. 33.
    Dierssen M, Gratacos M, Sahun I et al. Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction. Neurobiol Dis 2006; 24:403–418.CrossRefPubMedGoogle Scholar
  34. 34.
    Parain K, Murer MG, Yan Q et al. Reduced expression of brain-derived neurotrophic factor protein in Parkinson’s disease substantia nigra. NeuroReport 1999; 10:557–561.CrossRefPubMedGoogle Scholar
  35. 35.
    Porritt MJ, Batchelor PE, Howells DW. Inhibiting BDNF expression by antisense oligonucleotide infusion causes loss of nigral dopaminergic neurons. Exp Neurol 2005; 192:226–234.CrossRefPubMedGoogle Scholar
  36. 36.
    Momose Y, Murata M, Kobayashi K et al. Association studies of multiple candidate genes for Parkinson’s disease using single nucleotide polymorphisms. Ann Neurol 2002; 51:133–136.CrossRefPubMedGoogle Scholar
  37. 37.
    Karamohamed S, Latourelle JC, Racette BA et al. BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study. Neurology 2005; 65:1823–1825.CrossRefPubMedGoogle Scholar
  38. 38.
    Parsian A, Sinha R, Racette B et al. Association of a variation in the promoter region of the brain-derived neurotrophic factor gene with familial Parkinson’s disease. Parkinsonism Relat Disord 2004; 10:213–219.CrossRefPubMedGoogle Scholar
  39. 39.
    Hong CJ, Liu HC, Liu TY et al. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in Parkinson’s disease and age of onset. Neurosci Lett 2003; 353:75–77.CrossRefPubMedGoogle Scholar
  40. 40.
    Saarela MS, Lehtimaki T, Rinne JO et al. No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer’s or Parkinson’s disease. Folia Neuropathol 2006; 44:12–16.PubMedGoogle Scholar
  41. 41.
    Xiromerisiou G, Hadjigeorgiou GM, Eerola J et al. BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson’s disease in diverse ethnic groups. Neurosci Lett 2007; 415:59–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol 2001; 2:REVIEWS3005.Google Scholar
  43. 43.
    Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000; 7:165–197.CrossRefPubMedGoogle Scholar
  44. 44.
    Unsicker K, Reuss B, von Bohlen und Halbach O. Fibroblast growth factors in brain functions. In: Lajtha A, Lim R, eds. Handbook of Neurochemistry and Molecular Neurobiology. Neuroactive Proteins and Peptides. New York, Heidelberg: Springer; 2006:93–122.CrossRefGoogle Scholar
  45. 45.
    Bean AJ, Elde R, Cao YH et al. Expression of acidic and basic fibroblast growth factors in the substantia nigra of rat, monkey and human. Proc Natl Acad Sci USA 1991; 88:10237–10241.CrossRefPubMedGoogle Scholar
  46. 46.
    Cintra A, Cao YH, Oellig C et al. Basic FGF is present in dopaminergic neurons of the ventral midbrain of the rat. NeuroReport 1991; 2:597–600.PubMedCrossRefGoogle Scholar
  47. 47.
    Bean AJ, Oellig C, Pettersson RF et al. Differential expression of acidic and basic FGF in the rat substantia nigra during development. NeuroReport 1992; 3:993–996.CrossRefPubMedGoogle Scholar
  48. 48.
    Ferrari G, Minozzi MC, Toffano G et al. Basic fibroblast growth factor promotes the survival and development of mesencephalic neurons in culture. Dev Biol 1989; 133:140–147.CrossRefPubMedGoogle Scholar
  49. 49.
    Ferrari G, Minozzi MC, Toffano G et al. Basic fibroblast growth factor affects the survival and development of mesencephalic neurons in culture. Adv Exp Med Biol 1990; 265:93–99.PubMedGoogle Scholar
  50. 50.
    Otto D, Unsicker K. Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J Neurosci 1990; 10:1912–1921.PubMedGoogle Scholar
  51. 51.
    Park TH, Mytilineou C. Protection from 1-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP(+)-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF. Brain Res 1992; 599:83–97.CrossRefPubMedGoogle Scholar
  52. 52.
    Chadi G, Moller A, Rosen L et al. Protective actions of human recombinant basic fibroblast growth factor on MPTP-lesioned nigrostriatal dopamine neurons after intraventricular infusion. Exp Brain Res 1993; 97:145–158.CrossRefPubMedGoogle Scholar
  53. 53.
    Date I, Yoshimoto Y, Imaoka T et al. Enhanced recovery of the nigrostriatal dopaminergic system in MPTP-treated mice following intrastriatal injection of basic fibroblast growth factor in relation to aging. Brain Res 1993; 621:150–154.CrossRefPubMedGoogle Scholar
  54. 54.
    Otto D, Unsicker K. FGF-2-mediated protection of cultured mesencephalic dopaminergic neurons against MPTP and MPP+: specificity and impact of culture conditions, nondopaminergic neurons and astroglial cells. J Neurosci Res 1993; 34:382–393.CrossRefPubMedGoogle Scholar
  55. 55.
    Casper D, Blum M. Epidermal growth factor and basic fibroblast growth factor protect dopaminergic neurons from glutamate toxicity in culture. J Neurochem 1995; 65:1016–1026.PubMedCrossRefGoogle Scholar
  56. 56.
    Shults CW, Ray J, Tsuboi K et al. Fibroblast growth factor-2-producing fibroblasts protect the nigrostrital dopaminergic system from 6-hydroxydopamine. Brain Res 2000; 883:192–204.CrossRefPubMedGoogle Scholar
  57. 57.
    Leonard S, Luthman D, Logel J et al. Acidic and basic fibroblast growth factor mRNAs are increased in striatum following MPTP-induced dopamine neurofiber lesion: assay by quantitative PCR. Brain Res Mol Brain Res 1993; 18:275–284.CrossRefPubMedGoogle Scholar
  58. 58.
    Rufer M, Wirth SB, Hofer A et al. Regulation of connexin-43, GFAP and FGF-2 is not accompanied by changes in astroglial coupling in MPTP-lesioned, FGF-2-treated parkinsonian mice. J Neurosci Res 1996; 46:606–617.CrossRefPubMedGoogle Scholar
  59. 59.
    Giacobini MM, Stromberg I, Almstrom S et al. Fibroblast growth factors enhance dopamine fiber formation from nigral grafts. Brain Res Dev Brain Res 1993; 75:65–73.CrossRefPubMedGoogle Scholar
  60. 60.
    Mayer E, Fawcett JW, Dunnett SB. Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons—II. Effects on nigral transplants in vivo. Neuroscience 1993; 56:389–398.CrossRefPubMedGoogle Scholar
  61. 61.
    Takayama H, Ray J, Raymon HK et al. Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson’s disease. Nat Med 1995; 1:53–58.CrossRefPubMedGoogle Scholar
  62. 62.
    Timmer M, Muller-Ostermeyer F, Kloth V et al. Enhanced survival, reinnervation and functional recovery of intrastriatal dopamine grafts contransplanted with Schwann cells overexpressing high molecular weight FGF-2 isoforms. Exp Neurol 2004; 187:118–136.CrossRefPubMedGoogle Scholar
  63. 63.
    Zechel S, Jarosik J, Kiprianova I et al. FGF-2 deficiency does not alter vulnerability of the dopaminergic nigrostriatal system towards MPTP intoxication in mice. Eur J Neurosci 2006; 23:1671–1675.CrossRefPubMedGoogle Scholar
  64. 64.
    Timmer M, Cesnulevicius K, Winkler C et al. Fibroblast growth factor (FGF)-2 and FGF receptor 3 are required for the development of the substantia nigra and FGF-2 plays a crucial role for the rescue of dopaminergic neurons after 6-hydroxydopamine lesion. J Neurosci 2007; 27:459–471.CrossRefPubMedGoogle Scholar
  65. 65.
    von Bohlen und Halbach, O. Modeling neurodegenerative diseases in vivo review. Neurodegenerative Dis. 2006; 2:313–320.Google Scholar
  66. 66.
    Ohmachi S, Watanabe Y, Mikami T et al. FGF-20, a novel neurotrophic factor, preferentially expressed in the substantia nigra pars compacta of rat brain. Biochem Biophys Res Commun 2000; 277:355–360.CrossRefPubMedGoogle Scholar
  67. 67.
    Grothe C, Timmer M, Scholz T et al. Fibroblast growth factor-20 promotes the differentiation of Nurr1-overexpressing neural stem cells into tyrosine hydroxylase-positive neurons. Neurobiol Dis 2004; 17:163–170.CrossRefPubMedGoogle Scholar
  68. 68.
    Murase S, McKay RD. A specific survival response in dopamine neurons at most risk in Parkinson’s disease. J Neurosci 2006; 26:9750–9760.CrossRefPubMedGoogle Scholar
  69. 69.
    van der Walt JM, Noureddine MA, Kittappa R et al. Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. Am J Hum Genet 2004; 74:1121–1127.CrossRefPubMedGoogle Scholar
  70. 70.
    Satake W, Mizuta I, Suzuki S et al. Fibroblast growth factor 20 gene and Parkinson’s disease in the Japanese population. NeuroReport 2007; 18:937–940.CrossRefPubMedGoogle Scholar
  71. 71.
    Clarimon J, Xiromerisiou G, Eerola J et al. Lack of evidence for a genetic association between FGF20 and Parkinson’s disease in Finnish and Greek patients. BMC Neurol 2005; 5:11.CrossRefPubMedGoogle Scholar
  72. 72.
    Blum M. A null mutation in TGF-alpha leads to a reduction in midbrain dopaminergic neurons in the substantia nigra. Nat Neurosci 1998; 1:374–377.CrossRefPubMedGoogle Scholar
  73. 73.
    Nikkah G, Odin P, Smits A et al. Platelet-derived growth factor promotes survival of rat and human mesencephalic dopaminergic neurons in culture. Exp Brain Res 1993; 92:516–523.Google Scholar
  74. 74.
    Mohapel P, Frielingsdorf H, Haggblad J et al. Platelet-derived growth factor (PDGF-BB) and brain-derived neurotrophic factor (BDNF) induce striatal neurogenesis in adult rats with 6-hydroxydopamine lesions. Neuroscience 2005; 132:767–776.CrossRefPubMedGoogle Scholar
  75. 75.
    Hagg T, Varon S. Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo. Proc Natl Acad Sci USA 1993; 90:6315–6319.CrossRefPubMedGoogle Scholar
  76. 76.
    Akaneya Y, Takahashi M, Hatanaka H. Interleukin-1 beta enhances survival and interleukin-6 protects against MPP+ neurotoxicity in cultures of fetal rat dopaminergic neurons. Exp Neurol 1995; 136:44–52.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Interdisciplinary Center for Neurosciences, NeuroanatomyUniversity of HeidelbergHeidelbergGermany

Personalised recommendations