Original Article

Journal of Molecular Neuroscience

, Volume 20, Issue 2, pp 173-187

First online:

MANF

A new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons
  • Penka S. PetrovaAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology
  • , Andrei RaibekasAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology
  • , Jonathan PevsnerAffiliated withDepartment of Neurology, Kennedy Krieger Institute & Department of Neuroscience, Johns Hopkins School of Medicine
  • , Noel VigoAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology
  • , Mordechai AnafiAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology
  • , Mary K. MooreAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology
  • , Amy E. PeaireAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology
  • , Viji ShridharAffiliated withDepartment of Experimental Pathology, Division of Laboratory Medicine, Mayo Clinic
  • , David I. SmithAffiliated withDepartment of Experimental Pathology, Division of Laboratory Medicine, Mayo Clinic
    • , John KellyAffiliated withInstitute for Biological Studies, National Research Council of Canada
    • , Yves DurocherAffiliated withBiotechnology Research Institute, National Research Council of Canada, Animal Cell Technology Group
    • , John W. CommissiongAffiliated withPrescient NeuroPharma Inc., Laboratories of Protein Chemistry, Molecular Biology & Cell Biology Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

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