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PMID: 17188890 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Pro-NGF secreted by astrocytes promotes motor neuron cell death.

Molecular and cellular neurosciences ·Vol. 34 ·No. 2 ·2007-02-00 ·Pages 271-9

Domeniconi M, Hempstead BL, Chao MV

Abstract

It is well established that motor neurons depend for their survival on many trophic factors. In this study, we show that the precursor form of NGF (pro-NGF) can induce the death of motor neurons via engagement of the p75 neurotrophin receptor. The pro-apoptotic activity was dependent upon the presence of sortilin, a p75 co-receptor expressed on motor neurons. One potential source of pro-NGF is reactive astrocytes, which up-regulate the levels of pro-NGF in response to peroxynitrite, an oxidant and producer of free radicals. Indeed, motor neuron viability was sensitive to conditioned media from cultured astrocytes treated with peroxynitrite and this effect could be reversed using a specific antibody against the pro-domain of pro-NGF. These results are consistent with a role for activated astrocytes and pro-NGF in the induction of motor neuron death and suggest a possible therapeutic target for the treatment of motor neuron disease.

MeSH Terms
Adaptor Proteins, Vesicular Transport Analysis of Variance Animals Animals, Newborn Astrocytes/chemistry Cell Death/drug effects Cells, Cultured Culture Media, Conditioned/pharmacology Embryo, Mammalian Gene Expression/drug effects,physiology Homeodomain Proteins/metabolism LIM-Homeodomain Proteins Membrane Glycoproteins/metabolism Motor Neurons/drug effects Nerve Growth Factors/pharmacology Nerve Tissue Proteins/metabolism Peroxynitrous Acid/pharmacology Protein Precursors/pharmacology Rats Spinal Cord/cytology Transcription Factors
Chemicals
Adaptor Proteins, Vesicular Transport Culture Media, Conditioned Homeodomain Proteins LIM-Homeodomain Proteins Membrane Glycoproteins Nerve Growth Factors Nerve Tissue Proteins Protein Precursors Transcription Factors insulin gene enhancer binding protein Isl-1 pro-nerve growth factor, rat Peroxynitrous Acid sortilin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Domeniconi Marco
Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Hempstead Barbara L
Chao Moses V
References (69)
69 references, click to expand
  1. Pro-NGF isolated from the human brain affected by Alzheimer's disease induces neuronal apoptosis mediated by p75NTR.
    Am J Pathol. 2005 Feb;166(2):533-43 PMID: 15681836
  2. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin.
    J Neurosci. 2005 Jun 1;25(22):5455-63 PMID: 15930396
  3. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway.
    J Neurosci. 2005 Jun 29;25(26):6156-66 PMID: 15987945
  4. Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system.
    Mayo Clin Proc. 2005 Oct;80(10):1326-38 PMID: 16212146
  5. Interaction of survival and death signaling in basal forebrain neurons: roles of neurotrophins and proneurotrophins.
    J Neurosci. 2006 Jul 19;26(29):7756-66 PMID: 16855103
  6. Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase.
    J Biol Chem. 1999 Mar 26;274(13):8832-6 PMID: 10085125
  7. The role of p75NTR in modulating neurotrophin survival effects in developing motoneurons.
    Eur J Neurosci. 1999 May;11(5):1668-76 PMID: 10215920
  8. Regulation of nerve growth factor release by nitric oxide through cyclic GMP pathway in cortical glial cells.
    Mol Pharmacol. 1999 Aug;56(2):339-47 PMID: 10419553
  9. The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein.
    EMBO J. 2001 May 1;20(9):2180-90 PMID: 11331584
  10. Adaptative responses of spinal astrocytes to oxidative stress.
    Prog Brain Res. 2001;132:413-25 PMID: 11545008
  11. Regulation of cell survival by secreted proneurotrophins.
    Science. 2001 Nov 30;294(5548):1945-8 PMID: 11729324
  12. Neurotrophins: to cleave or not to cleave.
    Neuron. 2002 Jan 3;33(1):9-12 PMID: 11779474
  13. Matrix metalloproteinases in neuroinflammation.
    Glia. 2002 Sep;39(3):279-91 PMID: 12203394
  14. Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species.
    Glia. 1999 Nov;28(2):85-96 PMID: 10533053
  15. Programmed cell death of embryonic motoneurons triggered through the Fas death receptor.
    J Cell Biol. 1999 Nov 29;147(5):1049-62 PMID: 10579724
  16. Nerve growth factor (NGF) induces motoneuron apoptosis in rat embryonic spinal cord in vitro.
    Eur J Neurosci. 1999 Nov;11(11):3904-12 PMID: 10583479
  17. Nerve growth factor in glia and inflammatory cells of the injured rat spinal cord.
    J Neurochem. 2000 Feb;74(2):730-9 PMID: 10646525
  18. NGF-induced motoneuron cell death depends on the genetic background and motoneuron sub-type.
    Neuroreport. 2000 May 15;11(7):1473-7 PMID: 10841360
  19. Reduced apoptosis and increased lesion development in the flow-restricted carotid artery of p75(NTR)-null mutant mice.
    Circ Res. 2002 Sep 20;91(6):494-500 PMID: 12242267
  20. Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line.
    Gastroenterology. 2002 Oct;123(4):1135-43 PMID: 12360476
  21. ProNGF induces p75-mediated death of oligodendrocytes following spinal cord injury.
    Neuron. 2002 Oct 24;36(3):375-86 PMID: 12408842
  22. Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis.
    Neuroscience. 2003;116(3):685-94 PMID: 12573711
  23. Neurotrophins and their receptors: a convergence point for many signalling pathways.
    Nat Rev Neurosci. 2003 Apr;4(4):299-309 PMID: 12671646
  24. Expression and role of low-affinity nerve growth factor receptor (p75) in spinal motor neurons of aged rats following axonal injury.
    Dev Neurosci. 2003 Jan-Feb;25(1):65-71 PMID: 12876432
  25. Reduced p75NTR expression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis.
    Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Jun;4(2):100-5 PMID: 14506941
  26. Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice.
    J Neurochem. 2003 Nov;87(3):752-63 PMID: 14535957
  27. Neurotrophins and their receptors: signaling trios in complex biological systems.
    Cell Mol Life Sci. 2004 Jan;61(1):35-48 PMID: 14704852
  28. Sortilin is essential for proNGF-induced neuronal cell death.
    Nature. 2004 Feb 26;427(6977):843-8 PMID: 14985763
  29. Neurodegeneration or neuroprotection: the pivotal role of astrocytes.
    Neurochem Res. 2004 Mar;29(3):513-9 PMID: 15038599
  30. Differential regulation of neurotrophin expression in basal forebrain astrocytes by neuronal signals.
    J Neurosci Res. 2004 Apr 1;76(1):76-85 PMID: 15048931
  31. Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis.
    J Neurochem. 2004 Apr;89(2):464-73 PMID: 15056289
  32. Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury.
    Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6226-30 PMID: 15026568
  33. Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease.
    J Neuropathol Exp Neurol. 2004 Jun;63(6):641-9 PMID: 15217092
  34. Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice.
    J Neurosci Res. 2004 Oct 15;78(2):193-9 PMID: 15378612
  35. An immunohistochemical study of the nerve growth factor receptor in developing rats.
    J Neurosci. 1988 Sep;8(9):3481-98 PMID: 2845023
  36. Expression of nerve growth factor receptor mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons.
    Neuron. 1989 Jun;2(6):1605-13 PMID: 2560649
  37. Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide.
    J Biol Chem. 1991 Mar 5;266(7):4244-50 PMID: 1847917
  38. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor.
    Nature. 1991 Apr 25;350(6320):678-83 PMID: 1850821
  39. Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons.
    Brain Res. 1991 May 24;549(2):297-304 PMID: 1653083
  40. Purification of embryonic rat motoneurons by panning on a monoclonal antibody to the low-affinity NGF receptor.
    J Neurosci Methods. 1992 Aug;44(1):59-70 PMID: 1434751
  41. Distribution and relative density of p75 nerve growth factor receptors in the rat brain as a function of age and treatment with antibodies to nerve growth factor.
    Brain Res. 1992 Sep 25;591(2):223-38 PMID: 1446237
  42. Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death.
    Nature. 1992 Dec 24-31;360(6406):753-5 PMID: 1281520
  43. Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section.
    Nature. 1992 Dec 24-31;360(6406):757-9 PMID: 1465147
  44. A motor neuron-specific epitope and the low-affinity nerve growth factor receptor display reciprocal patterns of expression during development, axotomy, and regeneration.
    J Comp Neurol. 1993 Feb 15;328(3):351-63 PMID: 7680051
  45. Neurotrophins promote motor neuron survival and are present in embryonic limb bud.
    Nature. 1993 May 20;363(6426):266-70 PMID: 8487864
  46. Spinal cord motoneurons express p75NGFR and p145trkB mRNA in amyotrophic lateral sclerosis.
    Brain Res. 1993 Sep 3;621(1):111-5 PMID: 8221061
  47. Neurotrophin 4/5 is a trophic factor for mammalian facial motor neurons.
    Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3304-8 PMID: 8159743
  48. GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle.
    Science. 1994 Nov 11;266(5187):1062-4 PMID: 7973664
  49. Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF.
    Nature. 1995 Jan 26;373(6512):344-6 PMID: 7830769
  50. Functional interactions of neurotrophins and neurotrophin receptors.
    Annu Rev Neurosci. 1995;18:223-53 PMID: 7605062
  51. A potential interaction of p75 and trkA NGF receptors revealed by affinity crosslinking and immunoprecipitation.
    J Neurosci Res. 1995 Mar 1;40(4):557-63 PMID: 7616616
  52. Trophic factor response to neuronal stimuli or injury.
    Curr Opin Neurobiol. 1995 Jun;5(3):350-7 PMID: 7580158
  53. Altered NGF protein levels in different brain areas after immunolesion.
    J Neurosci Res. 1996 Jan 15;43(2):213-23 PMID: 8820969
  54. Expression of nerve growth factor, p75, and trk in the somatosensory and motor cortices of mature rats: evidence for local trophic support circuits.
    Somatosens Mot Res. 1995;12(3-4):329-42 PMID: 8834306
  55. The response of motoneurons to neurotrophins.
    Neurochem Res. 1996 Jul;21(7):831-41 PMID: 8873088
  56. Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75.
    Nature. 1996 Oct 24;383(6602):716-9 PMID: 8878481
  57. Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography.
    J Biol Chem. 1997 Feb 7;272(6):3599-605 PMID: 9013611
  58. Neurotrophic activity in cytokine-activated astrocytes.
    Keio J Med. 1997 Jun;46(2):55-60 PMID: 9212587
  59. Regulation of nerve growth factor secretion and mRNA expression by bacterial lipopolysaccharide in primary cultures of rat astrocytes.
    J Neurosci Res. 1997 Sep 1;49(5):569-75 PMID: 9302078
  60. Reactive astrocytes: cellular and molecular cues to biological function.
    Trends Neurosci. 1997 Dec;20(12):570-7 PMID: 9416670
  61. Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor.
    J Neurobiol. 1998 Jan;34(1):1-9 PMID: 9469614
  62. Astrocytes are the major source of nerve growth factor upregulation following traumatic brain injury in the rat.
    Exp Neurol. 1998 Feb;149(2):301-9 PMID: 9500953
  63. Neurotrophin receptors: mediators of life and death.
    Brain Res Brain Res Rev. 1998 May;26(2-3):295-301 PMID: 9651545
  64. The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor.
    J Biol Chem. 1998 Oct 9;273(41):26273-6 PMID: 9756851
  65. Peroxynitrite induces covalent dimerization of epidermal growth factor receptors in A431 epidermoid carcinoma cells.
    J Biol Chem. 1998 Nov 27;273(48):31860-6 PMID: 9822654
  66. Changes of NGF presence in nonneuronal cells in response to experimental allergic encephalomyelitis in Lewis rats.
    Exp Neurol. 1998 Nov;154(1):41-6 PMID: 9875266
  67. P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp.
    Nature. 2002 Nov 7;420(6911):74-8 PMID: 12422217
  68. Cardiotrophin-1 requires LIFRbeta to promote survival of mouse motoneurons purified by a novel technique.
    J Neurosci Res. 1999 Jan 1;55(1):119-26 PMID: 9890440
  69. p75 neurotrophin receptor expression is induced in apoptotic neurons after seizure.
    J Neurosci. 1999 Aug 15;19(16):6887-96 PMID: 10436046
Article Info
Journal
Molecular and cellular neurosciences
Abbr.
Mol Cell Neurosci
ISSN
1044-7431
DOI
10.1016/j.mcn.2006.11.005
Published
2007-02-00
Epub
2006-00-26
Pages
271-9
Language
English
Region
United States
NLM ID
9100095
PMCID
PMC2570110
Subset
IM
Grants
NICHD NIH HHS · HD023315 · United States
NICHD NIH HHS · P01 HD023315 · United States
NINDS NIH HHS · NS21072 · United States
NINDS NIH HHS · R01 NS021072 · United States
NICHD NIH HHS · P01 HD023315-200002 · United States
NINDS NIH HHS · R01 NS021072-22 · United States
NIA NIH HHS · R01 AG025970 · United States
NINDS NIH HHS · R56 NS021072 · United States
External Links
PubMed source DOI: 10.1016/j.mcn.2006.11.005 PMC Full Text View journal details
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