A synthetic peptide modeled on PDNF, Chagas' disease parasite neurotrophic factor, promotes survival and differentiation of neuronal cells through TrkA receptor.
The human parasite Trypanosoma cruzi, the agent of Chagas' disease, expresses a membrane-bound neuraminidase/trans-sialidase, also known as parasite-derived neurotrophic factor, PDNF, because it binds and activates nerve growth factor (NGF) receptor TrkA in neuronal cells. Here, we identify a 21 amino acid region (425GNASQNVWEDAYRCVNASATAN445) of PDNF that reproduces its neurotrophic activities. Synthetic peptide Y21, modeled on this sequence, induces survival and neurite outgrowth in primary dorsal root ganglion neurons. Y21 but not other PDNF-based peptides promotes survival and neurite extension in TrkA-expressing but not in TrkA-deficient PC12 cells. Y21 also enhances phosphorylation of TrkA in PC12 cells and activation of Erk1/2 and Akt kinases with kinetics distinct from that of PDNF. In addition, Y21 stimulates phosphorylation of cAMP response element-binding protein, CREB. Peptide Y21, therefore, reproduces several TrkA-dependent activities of PDNF and NGF. However, Y21 inhibits the binding of PDNF but not NGF to TrkA. Similarly, Y21 blocks PDNF- but not NGF-dependent phosphorylation of Erk1/2. These findings raise the possibility that Y21 reacts with a TrkA site required for the binding of PDNF but not NGF. The functioning of Y21 as TrkA agonist reproducing TrkA-dependent biological activities of PDNF should help elucidate the mechanism of PDNF activation of TrkA-expressing cells and the design of small drugs for the treatment of Chagas' and other neurodegenerative diseases.
Chuenkova
Marina V
MV
Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, Massachusetts 02111, USA.
PereiraPerrin
Mercio
M
D000595:Amino Acid Sequence; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000503:physiopathology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009439:Neuraminidase / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D016716:PC12 Cells; D010455:Peptides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000819:agonists / Q000187:drug effects / Q000502:physiology*
D006023:Glycoproteins; D010455:Peptides; C507413:Y(21) peptide; D050882:CREB-Binding Protein; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C069715:trans-sialidase; D009439:Neuraminidase