We are very grateful to Lotta Johanson for secretarial help, Annika Ahlsen and Maite Muñoz for technical assistance, and Anna Bosch for her support and advice in the use of confocal microscopy. Financial support was obtained from the BIOMED2 Program of the European Commission (grant BMH4-CT96-0273), CICYT (grants SAF96-0043 and SAF99-0019, Ministerio de Educación y Ciencia, Spain), La Marató de TV3 (grant 97-TV1009), the Swedish Medical Research Council (MFR, grant K98-12X-11563-03A), the Karolinska Institute, and the Jeanssonska and the Kapten Arthur Eriksson Foundations. E.P.-N. was a fellow of the European Molecular Biology Organization.

  • 1
    Alcántara S., Frisén J., Del Rio J.A., Soriano E., Barbacid M., Silos-Santiago I. (1997) TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death.J. Neurosci. 17 36233633.
  • 2
    Alexi T., Venero J.L., Hefti F. (1997) Protective effects of neurotrophin-4/5 and transforming growth factor-α on striatal neuronal phenotypic degeneration after excitotoxic lesioning with quinolinic acid.Neuroscience 78 7386.
  • 3
    Altar C.A., Cai N., Bliven T., Juhasz M., Conner J.M., Acheson A.L., Lindsay R., Wiegand S.J. (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain.Nature 389 856860.
  • 4
    Anderson K.D., Panayotatos N., Corcoran T.L., Lindsay R.M. (1996) Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease.Proc. Natl. Acad. Sci. USA 93 73467351.
  • 5
    Ardelt A.A., Flairs N.A., Roth K.A. (1994) Neurotrophin-4 selectively promotes survival of striatal neurons in organotypic culture.Brain Res. 647 340344.
  • 6
    Arenas E. & Persson H. (1994) Neurotrophin-3 prevents the death of adult central noradrenergic neurons in vivo. Nature 367 368371.
  • 7
    Arenas E., Aring;kerud P., Wong V., Boylan C., Persson H., Lindsay R.M., Altar C.A. (1996) Effects of BDNF and NT-4/5 on striatonigral neuropeptides or nigral GABA neurons in vivo. Eur. J. Neurosci. 8 17071717.
  • 8
    Barbacid M. (1994) The Trk family of neurotrophin receptors.J. Neurobiol. 25 13861403.
  • 9
    Beal M.F., Kowall N.W., Ellison D.W., Mazurek M.F., Swartz K.J., Martin J.B. (1986) Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid.Nature 321 168171.
  • 10
    Bemelmans A.P., Horellou P., Pradier L., Brunet I., Colin P., Mallet J. (1999) Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer.Hum. Gene Ther. 10 29872997.
  • 11
    Canals J.M., Checa N., Marco S., Michels A., Pérez-Navarro E., Alberch J. (1999) The neurotrophin receptors TrkA, TrkB and TrkC are differentially regulated after excitotoxic lesion in rat striatum.Mol. Brain Res. 69 242248.
  • 12
    Carlock L., Walker P.D., Shan Y., Gutridge K. (1995) Transcription of the Huntington disease gene during the quinolinic acid cascade.Neuroreport 6 11211124.
  • 13
    Carter B.D. & Lewin G.R. (1997) Neurotrophins live or let die: does p75NTR decide?Neuron 18 187190.
  • 14
    Carter B.D., Zirrgiebel U., Barde Y. -A. (1995) Differential regulation of p21ras activation in neurons by nerve growth factor and brain-derived neurotrophic factor.J. Biol. Chem. 270 2175121757.
  • 15
    Coggeshall R.E. (1992) A consideration of neuronal counting methods.Trends Neurosci. 15 913.
  • 16
    Connor B. & Dragunow M. (1998) The role of neuronal growth factors in neurodegenerative disorders of the human brain.Brain Res. Rev. 27 139.
  • 17
    Constantini L.C., Feinstein S.C., Radeke M.J., Snyder-Keller A. (1999) Compartmental expression of trkB receptor protein in the developing striatum.Neuroscience 89 505513.
  • 18
    DiFiglia M. (1990) Excitotoxic injury of the neostriatum: a model for Huntington's disease.Trends Neurosci. 13 286289.
  • 19
    Ernfors P., Merlio J., Persson H. (1992) Cells expressing mRNA for neurotrophins and their receptors during embryonic rat development.Eur. J. Neurosci. 4 11401158.
  • 20
    Ferrer I., Martín F., Serrano T., Reiriz J., Pérez-Navarro E., Alberch J., Macaya A., Planas A. (1995) Both apoptosis and necrosis occur following intrastriatal administration of excitotoxins.Acta Neuropathol. (Berl.) 90 504510.
  • 21
    Ferrer I., Ballabriga J., Marti E., Pérez-Navarro E., Alberch J., Arenas E. (1998) BDNF up-regulates trkB protein and prevents the death of CA1 neurons following transient forebrain ischemia.Brain Pathol. 8 253261.
  • 22
    Frank L., Ventimiglia R., Anderson K., Lindsay R.M., Rudge J.S. (1996) BDNF down-regulates neurotrophin responsiveness, TrkB protein and TrkB mRNA levels in cultured rat hippocampal neurons.Eur. J. Neurosci. 8 12201230.
  • 23
    Frim D.M., Uhler T.A., Short M.P., Ezzedine Z.D., Klagsbrun M., Breakefield X.O., Isacson O. (1993) Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxic lesions.Neuroreport 4 367370.
  • 24
    Goldberg Y.P., Nicholson D.W., Rasper D.M., Kalchman M.A., Koide N.A., Vaillancourt J.P., Hayden M.R. (1996) Cleavage of huntingtin by apopain, a preapoptotic cystein protease, is modulated by the polyglutamate tract.Nat. Genet. 13 442449.
  • 25
    Han B.H.D, 'Costa A., Back S.A., Parsadanian M., Patel S., Shah A.R., Gidday J.M., Srinivasan A., Deshmukh M., Holtzman D.M. (2000) BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia.Neurobiol. Dis. 7 3853.
  • 26
    Hefti F. (1994) Neurotrophic factor therapy for nervous system degenerative disorders.J. Neurobiol. 25 14181435.
  • 27
    Hughes P.E., Alexi T., Yoshida T., Schreiber S.S., Knusel B. (1996) Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 messenger RNA and protein and p53-inducible genes BAX and GADD-45 in brain areas showing DNA fragmentation. Neuroscience 74 11431160.
  • 28
    Knüsel B., Kaplan D.R., Hefti F. (1996) Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation.Exp. Neurol. 139 121130.
  • 29
    MacDonald M.E. & Gusella J.F. (1996) Huntington's disease: translating CAG repeat into a pathogenic mechanism.Curr. Opin. Neurobiol. 6 638643.
  • 30
    Mangiarini L., Sathasivam K., Seller M., Cozens B., Harper A., Hetherington C., Lawton M., Trottier Y., Lehrach H., Davies S.W., Bates G.P. (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neuropathological phenotype in transgenic mice.Cell 87 493506.
  • 31
    Martínez-Serrano A. & Björklund A. (1996) Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells.J. Neurosci. 16 46044616.
  • 32
    Merlio J., Ernfors P., Jaber M., Persson H. (1992) Molecular cloning of rat trkC and distribution of cells expressing messenger RNAs for members of the trk family in the rat central nervous system.Neuroscience 51 513532.
  • 33
    Miranda R.C., Sohrabji F., Toran-Allerand D. (1993) Neuronal colocalization of mRNAs for neurotrophins and their receptors in the developing central nervous system suggests a potential for autocrine interactions.Proc. Natl. Acad. Sci. USA 90 64396443.
  • 34
    Mufson E.J., Kroin J.S., Sendera T.J., Sobreviela T. (1999) Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.Prog. Neurobiol. 157 451484.
  • 35
    Nakao N., Kokaia Z., Odin P., Lindvall O. (1995a) Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons.Exp. Neurol. 131 110.
  • 36
    Nakao N., Brundin P., Funa K., Lindvall O., Odin P. (1995b) Trophic and protective actions of brain-derived neurotrophic factor on striatal DARPP-32 containing neurons in vitro.Dev. Brain Res. 90 92101.
  • 37
    Neveu I. & Arenas E. (1996) Neurotrophins promote the survival and development of neurons in the cerebellum of hypothyroid rats in vivo.J. Cell Biol. 133 631646.
  • 38
    Ona V.O., Li M., Vonsattel J.P.G., Andrews L.J., Khan S.Q., Chung W.M., Frey A.S., Menon A.S., Li X., Stieg P.E., Yuan J., Penney J.B., Young A.B., Cha J., Friedlander R.M. (1999) Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.Nature 399 263267.
  • 39
    Pérez-Navarro E., Arenas E., Reiriz J., Calvo N., Alberch J. (1996) Glial cell-line derived neurotrophic factor (GDNF) protects striatal calbindin immunoreactive neurons from excitotoxic damage.Neuroscience 75 345352.
  • 40
    Pérez-Navarro E., Alberch J., Neveu I., Arenas E. (1999a) BDNF, NT-3 and NT-4/5 differentially regulate the phenotype and prevent degenerative changes of striatal projection neurons after excitotoxicity in vivo. Neuroscience 91 12571264.
  • 41
    Pérez-Navarro E., Arenas E., Marco S., Alberch J. (1999b) Intrastriatal grafting of a GDNF-producing cell line protects striatonigral neurons from quinolinic acid excitotoxicity in vivo. Eur. J. Neurosci. 11 241249.
  • 42
    Petersén Å., Mani K. & Brundin P. (1999) Recent advances in the pathogenesis of Huntington's disease.Exp. Neurol. 157 118.
  • 43
    Portera-Cailliau C., Hedreen J.C., Price D.L., Koliatsos V.E. (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models.J. Neurosci. 15 37753787.
  • 44
    Reiner A., Albin R.L., Anderson K.D., D'Amato C.J., Penney J.B., Young A.B. (1988) Differential loss of striatal projection neurons in Huntington disease.Proc. Natl. Acad. Sci. USA 85 57335737.
  • 45
    Richfield E.K., Maguire-Zeiss K.A., Vonkeman H.E., Voorn P. (1995) Preferential loss of preproenkephalin versus preprotachykinin neurons from the striatum of Huntington's disease patients.Ann. Neurol. 38 852861.
  • 46
    Segal R.A. & Greenberg M.E. (1996) Intracellular signaling pathways activated by neurotrophic factors.Annu. Rev. Neurosci. 19 463489.
  • 47
    Segal R.A., Bhattacharyya A., Rua L.A., Alberta J.A., Stephens R.M., Kaplan D.R., Stiles C.D. (1996) Differential utilization of Trk autophosphorylation sites.J. Biol. Chem. 271 2017520181.
  • 48
    Seroogy K.B. & Gall C. (1993) Expression of neurotrophins by midbrain dopaminergic neurons.Exp. Neurol. 124 119128.
  • 49
    Springer J.E. & Kitzman P.H. (1998) Neuroprotective strategies involving the neurotrophins and their signaling pathways, inNeuroprotective Signal Transduction (Mattson M. P., ed), pp. 122. Humana Press, Totowa, New Jersey.
  • 50
    Tamatani M., Ogawa S., Tohyama M. (1998) Roles of Bcl-2 and caspases in hypoxia-induced neuronal cell death: a possible neuroprotective mechanism of peptide growth factors.Mol. Brain Res. 58 2739.
  • 51
    Tatter S.B., Galpern W.R., Hoogeveen A.T., Isacson O. (1995) Effects of striatal excitotoxicity on huntingtin-like immunoreactivity.Neuroreport 6 11251129.
  • 52
    Timmusk T., Belluardo N., Metsis M., Persson H. (1993) Widespread and developmentally regulated expression of neurotrophin-4 mRNA in rat brain and peripheral tissues.Eur. J. Neurosci. 5 605613.
  • 53
    Thomas L.B., Gates D.J., Richfield E.K., O'Brien T.F., Schweitzer J.B., Steindler D.A. (1995) DNA end labeling (TUNEL) in Huntington's disease and other neuropathological conditions.Exp. Neurol. 133 265272.
  • 54
    Ventimiglia R., Mather P.E., Jones B.E., Lindsay R.M. (1995) The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur. J. Neurosci. 7 213222.
  • 55
    Widmer H.R. & Hefti F. (1994) Neurotrophin-4/5 promotes survival and differentiation of rat striatal neurons developing in culture.Eur. J. Neurosci. 6 16691679.