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Journal of Molecular Neuroscience

, Volume 20, Issue 2, pp 173–187 | Cite as

MANF

A new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons
  • Penka S. Petrova
  • Andrei Raibekas
  • Jonathan Pevsner
  • Noel Vigo
  • Mordechai Anafi
  • Mary K. Moore
  • Amy E. Peaire
  • Viji Shridhar
  • David I. Smith
  • John Kelly
  • Yves Durocher
  • John W. Commissiong
Original Article

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 

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Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Penka S. Petrova
    • 1
  • Andrei Raibekas
    • 1
  • Jonathan Pevsner
    • 2
  • Noel Vigo
    • 1
  • Mordechai Anafi
    • 1
  • Mary K. Moore
    • 1
  • Amy E. Peaire
    • 1
  • Viji Shridhar
    • 3
  • David I. Smith
    • 3
  • John Kelly
    • 4
  • Yves Durocher
    • 5
  • John W. Commissiong
    • 1
  1. 1.Prescient NeuroPharma Inc., Laboratories of Protein ChemistryMolecular Biology & Cell BiologyTorontoCanada
  2. 2.Department of Neurology, Kennedy Krieger Institute & Department of NeuroscienceJohns Hopkins School of MedicineBaltimoreUSA
  3. 3.Department of Experimental Pathology, Division of Laboratory MedicineMayo ClinicRochesterUSA
  4. 4.Institute for Biological StudiesNational Research Council of CanadaOttawaCanada
  5. 5.Biotechnology Research InstituteNational Research Council of Canada, Animal Cell Technology GroupMontrealCanada

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