Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism.
Cyclized peptides corresponding to beta-loop regions of NGF were purified by HPLC and assayed for neurotrophic activity using DRG neurons. Peptides with the highest activity corresponded to loop region 29-35, a domain likely to interact with the p75 receptor. Unexpectedly, activity was confined to late-eluting HPLC fractions containing peptide multimers and primarily promoted neuronal survival without neurite outgrowth. Directed synthesis of dimer and monomer cyclized peptides demonstrated that dimers acted as partial NGF agonists in that they had both survival-promoting and NGF-inhibiting activity while monomer and linear peptides were inactive. Dimer activity was not affected by the Trk inhibitor K252a but was blocked by p75 receptor antibody and absent using p75 null mutant neurons. These studies suggest that region 29-35 peptide derivatives inhibit neuronal death via a structure- and p75-dependent mechanism.
Longo
F M
FM
Department of Neurology, UCSF/VAMC, San Francisco, California 94121, USA.
Manthorpe
M
M
Xie
Y M
YM
Varon
S
S
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001681:Biological Assay; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016501:Neurites / Q000737:chemistry / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D009479:Neuropeptides / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology; D011487:Protein Conformation; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism
D000906:Antibodies; D004220:Disulfides; D009479:Neuropeptides; D010446:Peptide Fragments; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor