Summary
Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopaminergic neurons. Since dopaminergic neurons degenerate in Parkinson's disease, this factor is a potential therapeutical tool that may save dopaminergic neurons during the pathological process. Moreover, a reduced GDNF expression may be involved in the pathophysiology of the disease. In this study, we tested whether altered GDNF production may participate in the mechanism of cell death in this disease. GDNF gene expression was analyzed by in situ hybridization using riboprobes corresponding to a sequence of the exon 2 human GDNF gene. Experiments were performed on tissue sections of the mesencephalon and the striatum from 8 patients with Parkinson's disease and 6 control subjects matched for age at death and for post mortem delay. No labelling was observed in either group of patients. This absence of detectable expression could not be attributed to methodological problems as a positive staining was observed using the same probes for sections of astroglioma biopsies from human adults and for sections of a newborn infant brain obtained at post-mortem. These data suggest that GDNF is probably expressed at a very low level in the adult human brain and its involvement in the pathophysiology of Parkinson's disease remains to be demonstrated. GDNF may represent a powerful new therapeutic agent for Parkinson's disease, however.
Similar content being viewed by others
References
Agid Y, Ruberg M, Javoy-Agid F, Hirsch EC, Raisman-Vozari R, Vyas S, Faucheux B, Michel P, Kastner A, Blanchard V, Damier P, Villares J, Zhang P (1993) Are dopaminergic neurons selectively vulnerable to Parkinson's disease? In: Narabayashi H, Nagatsu T, Yanagisawa N, Mizuno Y (eds) Advances in neurology, vol 60. Raven Press, New York, pp 148–164
Alexi T, Hefti F (1993) Trophic actions of transforming growth factor α on mesencephalic dopaminergic neurons developing in culture. Neuroscience 55: 903–918
Altar CA, Boylan CB, Fritsche M, Jones BE, Jackson C, Wiegand SJ, Lindsay RM, Hyman C (1994) Efficacy of brain-derived neurotrophic factor and neurotrophin-3 on neurochemical and behavioral deficits associated with partial nigrostriatal dopamine lesions. J Neurochem 63: 1021–1032
Anglade P, Blanchard V, Raisman-Vozari R, Faucheux B, Herrero MT, Obeso JA, Mouatt-Prigent A, Kastner A, Strada O, Javoy-Agid F, Agid Y, Hirsch EC (1996) Is dopaminergic cell death accompanied by concomitant nerve plasticity? In: Battistin L, Scarlato G, Caraceni T, Ruggieri S (eds) Advances in neurology, vol 69. Lippincott Raven Publishers, Philadelphia, pp 195–208
Beck K, Knüsel B, Hefti F (1993) The nature of the trophic action of brain-derived neurotrophic factor, des(1–3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopaminergic neurons developing in culture. Neuroscience 52: 855–866
Beck KD, Valverde J, Alexi T, Poulsen K, Moffat B, Vandlen RA, Rosenthal A, Hefti F (1995) Mesencephalic dopaminergic neurons protected by GDNF from axotomyinduced degeneration in the adult brain. Nature 373: 339–341
Bernard V, Gardiol A, Faucheux B, Bloch B, Agid Y, Hirsch EC (1996) Expression of glutamate receptors in the human and rat basal ganglia: effect of the dopaminergic denervation on AMPA receptor gene expression in the sriatopallidal complex in Parkinson's disease and rat with 6-OHDA lesion. J Comp Neurol 368: 553–568
Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20: 415–455
Blum M, Weickert CS (1995) GDNF mRNA expression in normal postnatal development, aging, and in Weaver mutant mice. Neurobiol Aging 16: 925–929
Bowenkamp KE, Hoffman AF, Gerhardt GA, Henry MA, Biddle PT, Hoffer BJ, Granholm A-CE (1995) Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons. J Comp Neurol 355: 479–489
Brana C, Charron G, Aubert I, Carles D, Martin-Negrier ML, Fournier MC, Vital C, Bloch B (1995) Ontogeny of the striatal neurons expressing neuropeptide genes in the human fetus and neonate. J Comp Neurol 360: 2–19
Brooks DJ, Ibanez V, Sawle GV, Playford ED, Quinn N, Mathias CJ, Lees AJ, Marsden DD, Bannister R, Frackowiak RS (1992) Striatal D2 receptor status in patients with Parkinson's disease, strionigral degeneration and progressive supranuclear palsy measured with11C raclopride and positron emission tomography. Ann Neurol 31: 184–192
Cristina N, Chatellard-Causse C, Manier M, Feuerstein C (1995) GDNF: existence of a second transcript in the brain. Mol Brain Res 32: 354–357
Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 52: 1–6
Hadjiconstantinou M, Fitkin JG, Dalia A, Neff NH (1991) Epidermal growth factor enhances striatal dopaminergic parameters in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse. J Neurochem 57: 479–482
Hagg T, Varon S (1993) Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo. Proc Natl Acad Sci USA 90: 6315–6319
Humpel C, Hoffer B, Strömberg I, Bektesh S, Collins F, Olson L (1994) Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in response to kainate-induced excitation. Neuroscience 59: 791–795
Hyman C, Juhasz M, Jackson C, Wright P, Ip NY, Lindsay M (1994) 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 14: 335–347
Knüsel B, Michel PP, Schwaber JS, Hefti F (1990) Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast factor, epidermal growth factor, insulin, and insulin-like growth factor I and II. J Neurosci 10: 558–570
Krieglstein K, Suter-Crazzolara C, Fischer WH, Unsicker K (1995) TGF-beta superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. EMBO J 14: 736–742
Levy R, Herrero T, Ruberg M, Villares J, Faucheux B, Guridi J, Guillen, Luquin MR, Javoy-Agid F, Obeso JA, Agid Y, Hirsch EC (1995a) Effects of nigrostriatal denervation and L-Dopa therapy on the GABAergic neurons of the striatum in the MPTP-treated monkeys and Parkinson's disease: an in situ hybridization study of GAD67 mRNA. Eur J Neurosci 7: 1199–1209
Levy R, Vila M, Herrero MT, Faucheux B, Agid Y, Hirsch EC (1995b) Striatal expression of substance P and methionin-enkephalin genes in patients with Parkinson's disease. Neurosci Lett 199: 220–224
Lin L-F H, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell linederived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1130–1132
Mayer E, Dunnett SB, Pellitteri R, Fawcett JW (1993) Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons. I. Effects in vitro. Neuroscience 56: 379–388
Murray KD, Gall CM, Jones EG, Isackson PJ (1994) Differential regulation of brain-derived neurotrophic factor and type II calcium/calmoduline-dependent protein kinase messenger RNA expression in Alzheimer's disease. Neuroscience 60: 37–48
Olson L, Humpel C, Strömberg I, Hoffer B, Collins F (1993) Brain sites of glial-cell-line derived neurotrophic factor synthesis as revealed by in situ hybridization. Soc Neurosci Abstr 19: 652
Otto D, Unsicker K (1990) Basic FGF reverses chemical and morphological deficits in the nigrostriatal system of MPTP-treated mice. J Neurosci 10: 1912–1921
Otto D, Unsicker K (1993) FGF-2-mediated protection of cultured mesencephalic dopaminergic neurons against MPTP and MPP+: specificity and impact of culture conditions, non-dopaminergic neurons, and astroglial cells. J Neurosci Res 34: 382–393
Phillips HS, Hains JM, Armanini M, Laramee GR, Johson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 7: 695–702
Poulsen KT, Armanini MP, Klein RD, Hynes MA, Phillips HS, Rosenthal A (1994) TGFβ2 and TGFβ3 are potent survival factors for midbrain dopaminergic neurons. Neuron 13: 1245–1252
Represa A, Niquet J, Pollard H, Ben-Ari Y (1995) Cell death, gliosis, and synaptic remodeling in the hippocampus of epileptic rats. J Neurobiol 26: 413–425
Schaar DG, Sieber B-A, Dreyfus CF, Black I (1993) Regional and cell-specific expression of GDNF in rat brain. Exp Neurol 124: 368–371
Schmidt-Kastner R, Tomac A, Hoffer B, Bektesh S, Rosenzweig B, Olson L (1994) Glial cell-line derived neurotrophic factor (GDNF) mRNA upregulation in striatum and cortical areas after pilocarpine-induced status epilepticus in rats. Mol Brain Res 26: 325–330
Scott SA, Mufson EJ, Weingartner JA, Skau KA, Crutcher KA (1995) Nerve growth factor in Alzheimer's disease: increased levels throughout the brain coupled with declines in nucleus basalis. J Neurosci 15: 6213–6221
Springer JE, Mu X, Bergmann LW, Trojanowski JQ (1994) Expression of GDNF mRNA in rat and human nervous tissue. Exp Neurol 127: 167–170
Springer JE, Seeburger JL, He J, Gabrea A, Blankenhorn EP, Bergman LW (1995) cDNA sequence and differential mRNA regulation of two forms of glial cell line-derived neurotrophic factor in Schwann cells and rat skeletal muscle. Exp Neurol 131: 47–52
Strömberg I, Björklund L, Johanson M, Tomac A, Collins F, Olson L, Hoffer B, Humpel C (1993) Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol 124: 401–412
Studer L, Spenger C, Seiler RW, Altar CA, Lindsay RM, Hyman C (1995) Comparison of the effects of the neurotrophins on the morphological structure of dopaminergic neurons in cultures of rats substantia nigra. Eur J Neurosci 7: 223–233
Suter-Crazzolara C, Unsicker K (1994) GDNF is expressed in two forms in many tissues outside the CNS. NeuroReport 5: 2486–2488
Tomac A, Lindqvist E, Lin L-F H, Ögren SO, Young D, Hoffer BJ, Olson L (1995) Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373: 335–339
Treanor J, Hefti F, Siegel M, Beck K (1995) Characterization of GDNF binding to putative GDNF receptor. Soc Neurosci Abstr 21: 1301
Unsicker K (1994) Growth factors in Parkinson's disease. Prog Growth Factor Res 5: 73–87
Vila M, Herrero MT, Levy R, Faucheux B, Ruberg M, Guillen J, Luquin MR, Guridi J, Javoy-Agid F, Agid Y, Obeso JA, Hirsch EC (1996) Consequences of nigrostriatal denervation on the γ-aminobutyric acidic neurons of substantia nigra pars reticulata and superior colliculus in parkinsonian syndromes. Neurology 46: 802–809
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hunot, S., Bernard, V., Faucheux, B. et al. Glial cell line-derived neurotrophic factor (GDNF) gene expression in the human brain: A post mortem in situ hybridization study with special reference to Parkinson's disease. J. Neural Transmission 103, 1043–1052 (1996). https://doi.org/10.1007/BF01291789
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01291789