MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons.
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 astrocyte 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 alpha-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.
Petrova
Penka
P
Laboratories of Protein Chemistry, Molecular Biology & Cell Biology, Prescient NeuroPharma Inc., 96 Skyway Avenue, Toronto, Ontario, Canada M9W 4Y9.
Raibekas
Andrei
A
Pevsner
Jonathan
J
Vigo
Noel
N
Anafi
Mordechai
M
Moore
Mary K
MK
Peaire
Amy E
AE
Shridhar
Viji
V
Smith
David I
DI
Kelly
John
J
Durocher
Yves
Y
Commissiong
John W
JW
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001483:Base Sequence / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002461:Cell Line, Transformed; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000302:isolation & purification*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000302:isolation & purification* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D018076:DNA, Complementary; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; C099695:MANF protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D004298:Dopamine