A new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons
Received: 20 December 2002 Accepted: 09 February 2003 DOI:
Cite this article as: Petrova, P.S., Raibekas, A., Pevsner, J. et al. J Mol Neurosci (2003) 20: 173. doi:10.1385/JMN:20:2:173 Abstract
We describe the discovery of a novel, 20 kDa, secreted human protein named mesencephalic astrocyte-derived neurotrophic factor, or MANF. The homologous, native molecule was initially derived from a rat mesencephalic type-1 astroycte cell line and recombinant MANF subcloned from a cDNA encoding human arginine-rich protein. MANF selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons. The discovery of MANF marks a more systematic approach in the search for astrocyte-derived, secreted proteins that selectively protect specific neuronal phenotypes. Compared to glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), MANF was more selective in the protection of dopaminergic neurons at lower (0.05–0.25 ng/mL) and middle (0.5–2.5 ng/mL) concentrations: MANF>GDNF>BDNF. GDNF was more selective at higher concentrations (25–50 ng/ml): GDNF>MANF>BDNF. Two domains in MANF of 39-AA and 109-AA respectively, and eight cysteines are conserved from
C. elegans to man. MANF is encoded by a 4.3 Kb gene with 4 exons, and is located on the short arm of human chromosome 3. The secondary structure is dominated by α-helices (47%) and random coils (37%). Studies to determine the localization of MANF in the brains of rat, monkey, and man, as well as the receptor, signaling pathways, and biologically active peptide mimetics are in progress. The selective, neuroprotective effect of MANF for dopaminergic neurons suggests that it may be indicated for the treatment of Parkinson’s disease. Index Entries Cell line secreted protein novel protein type-1 astrocyte neuroprotection phenotype specificity References
Abbott N. J. (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability.
Airaksinen M. S. and Saarma M. (2002) The gdnf family: signalling, biological functions and therapeutic value.
Nat. Rev Neurosci.
Albrecht P. J., Dahl J. P., Stoltzfus O. K., Levenson R., and Levison S. W. (2002) Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival.
Araque A., Carmignoto G., and Haydon P. G. (2001) Dynamic signaling between astrocytes and neurons.
Annu. Rev. Physiol.
Bassan M., Zamostiano R., Davidson A., Pinhasov A., Giladi E., Perl O., et al. (1999) Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide.
Beattie E. C., Stellwagen D., Morishita W., Bresnahan J. C., Ha B. K., Von Zastrow M., et al. (2002) Control of Synaptic Strength by Glial TNFalpha.
Brenneman D. E. and Gozes I. (1996) A femtomolar-acting neuroprotective peptide.
J. Clin. Invest.
Chao M. V. (1994) The p75 neurotrophin receptor.
Davies A. M. and Wright E. M. (1995) Neurotrophic factors: Neurotrophin autocrine loops.
Dreher Z., Tout S., and Stone J. (1994) Interactions of living astrocytes in vitro: Evidence of the development of contact spacing.
Durocher Y., Perret S., and Kamen A. (2002) High-level and high-throughput recombinant protein production by transient transfection of suspension-growing human 293-EBNA1 cells.
Nucleic Acid Res.
30, No. 2e9.
Forger N. G. and Breedlove S. M. (1987) Motoneuronal death during human fetal development.
J. Comp. Neurol.
Fraser D. D., Mudrick-Donnon L. A., and MacVicar B. A. (1994) Astrocytic GABA receptors.
Hansson E. and Rönnbäck L. (1990) Astrocytes in neurotransmission.
Cell. Mol. Biol.
Hashino E., Shero M., Junghans D., Rohrer H., Milbrandt J., and Johnson E. M. J. (2001) GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development.
Haydon P. G. (2001) GLIA: listening and talking to the synapse.
Nat Rev Neurosci
Heumann R. (1994) Neurotrophin signaling.
Curr. Opin. Neurobiol.
Hidalgo A., Kinrade E. F., and Georgiou M. (2001) The Drosophila neuregulin vein maintains glial survival during axon guidance in the CNS.
Hyman C., Hofer M., Barde Y.-A., Juhasz M., Yancopoulos G. D., Squinto S. P., and Lindsay R. M. (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra.
Jing S., Wen D., Yu Y., Holst P., Luo Y., Fang M., et al. (1996) GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF.
Kim W. T., Rioult M. G., and Cornell-Bell A. H. (1994) Glutamate-induced calcium signaling in astrocytes.
Kinrade E. F., Brates T., Tear G., and Hidalgo A. (2001) Roundabout signalling, cell contact and trophic support confine longitudinal glia and axons in the Drosophila CNS.
Kohara K., Kitamura A., Morishima M. and Tsumoto T. (2001) Activity-Dependent Transfer of Brain-Derived Neurotrophic Factor to Postsynaptic Neurons.
Korsching S. (1993) The neurotrophic factor concept: A reexamination.
Kruger G. and Morrison S. (2002) Brain repair by endogenous progenitors.
Levi-Montalcini R. (1987) The nerve growth factor 35 years later.
Levi-Montalcini R. and Hamburger V. (1951) Selective growth-stimulating effects of mouse sarcoma on sensory and sympathetic nervous system of the chick embryo.
J. Exp. Zool.
Li J., Kelly J. F., Chernushevich I., Harrison D. J., and Thibault P. (2000) Separation and identification of peptides from gel-isolated membrane proteins using a microfabricated device for combined capillary electrophoresis/nanoelectroscopy mass spectrometry.
Lin L.-F. H., Doherty D. H., Lile J. D., Bektesh S. and Collins F. (1993) GDNF: A glial cell-line derived neurotrophic factor for midbrain dopaminergic neurons.
Lin L.-F. H., Zhang T. J., Collins F., and Armes L. G. (1994) Purification and initial characterization of rat B49 glial cell line-derived neurotrophic factor.
Massagué J. (1996) Crossing the boundaries.
Nagler K., Mauch D. H., and Pfrieger F. W. (2001) Gliaderived signals induce synapse formation in neurones of the rat central nervous system.
J. Physiol. (Lond.)
Nakatomi H., Kuriu T., Okabe S., Yamamoto S., Hatano O., Kawahara N., et al. (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors.
Nedergaard M. (1994) Direct signaling from astrocytes to neurons in cultures of mammalian brain cells.
Nishi R. (1994) Target-derived molecules that influence the development of neurons in the avian ciliary ganglion.
O’Malley E. K., Sieber B.-A., Morrison R. S., Black I. B., and Dreyfus C. F. (1994) Nigral Type I astrocytes release a soluble factor that increases dopaminergic neuron survival through mechanisms distinct from basic fibroblast growth factor.
Panchision D. M., Martin-DeLeon P. A., Takeshima T., Johnston J. M., Shimoda K., Tsoulfas P., et al. (1998) An immortalized, type-1 astrocyte of mesencephalic origin source of a dopaminergic neurotrophic factor.
J. Mol. Neurosci.
Peaire A. E., Takeshima T., Johnston J. M., Wada-Isoe K., Nakashima K., and Commissiong J. W. (2003) Production of dopaminergic neurons for cell therapy in the treatment of Parkinson’s disease.
J. Neurosci. Meth.
Pinon L. G., Robinson M., and Davies A. M. (1995) High specificity of neurotrophins in the embryonic chicken trigeminal system.
Eur. J. Neurosci.
Purves D. (1986) The trophic theory of neural connections.
Salm A. K. and McCarthy K. D. (1992) The evidence for astrocytes as a target for central noradrenergic activity: Expression of adrenergic receptors.
Brain Res. Bull.
Shimoda K., Sauve Y., Marini A., Schwartz J. P., and Commissiong J. W. (1992) A high percentage yield of tyrosine hydroxylase-positive cells from rat E14 mesencephalic cell culture.
Shridhar V., Richard S., Shridhar R., et al. (1996) A gene from human chromosomal band 3p21.1 encodes a highly conserved arginine-rich-protein and is mutated in renal cell carcinomas.
Song H., Stevens C. F., and Gage F. H. (2002) Astroglia induce neurogenesis from adult stem cells.
Takeshima T., Johnston J. M., and Commissiong J. W. (1994) Mesencephalic type 1 astrocytes rescue dopaminergic neurons from death induced by serum deprivation.
Takeshima T., Shimoda K., Johnston J. M., and Commissiong J. W. (1996) Standardized methods to bioassay neurotrophic factors for dopaminergic neurons.
J. Neurosci. Meth.
Ullian E. M., Sapperstein S. K., Christopherson K. S., and Barres B. A. (2001) Control of synapse number by glia.
Van Wagoner N. J., Oh J. W., Repovic P., and Benveniste E. N. (1999) Interleukin-6 (IL-6) production by astrocytes: autocrine regulation by IL-6 and the soluble IL-6 receptor.
Vogel K. S. and Davies A. M. (1991) The duration of neurotrophic factor independence in early sensory neurons is matched to the time course of target field innervation.
Wichterle H., Lieberam I., Porter J. A., and Jessell T. M. (2002) Directed differentiation of embryonic stem cells into motor neurons.