Transmembrane Domain IV Confer Peptide Affinity Domain-Dependent Modulation by Ganglioside Knockout of p75 Does Not Alter Viability Peptide Function VIP and PACAP Neurodegeneration Tau and Synuclein 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 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. Journal of Molecular Neuroscience Copyright © 2003 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/03/20:173–187/$20.00 Journal of Molecular Neuroscience 173 Volume 20, 2003 *Author to whom all correspondence and reprint requests should be addressed: E-mail: [email protected] ORIGINAL ARTICLE