Cellular prion protein transduces neuroprotective signals.
To test for a role for the cellular prion protein (PrP(c)) in cell death, we used a PrP(c)-binding peptide. Retinal explants from neonatal rats or mice were kept in vitro for 24 h, and anisomycin (ANI) was used to induce apoptosis. The peptide activated both cAMP/protein kinase A (PKA) and Erk pathways, and partially prevented cell death induced by ANI in explants from wild-type rodents, but not from PrP(c)-null mice. Neuroprotection was abolished by treatment with phosphatidylinositol-specific phospholipase C, with human peptide 106-126, with certain antibodies to PrP(c) or with a PKA inhibitor, but not with a MEK/Erk inhibitor. In contrast, antibodies to PrP(c) that increased cAMP also induced neuroprotection. Thus, engagement of PrP(c) transduces neuroprotective signals through a cAMP/PKA-dependent pathway. PrP(c) may function as a trophic receptor, the activation of which leads to a neuroprotective state.
Chiarini
Luciana B
LB
Instituto de Biofísica da UFRJ, CCS, bloco G, Cidade Universitária, 21949-900, Rio de Janeiro, Brasil.
Freitas
Adriana R O
AR
Zanata
Silvio M
SM
Brentani
Ricardo R
RR
Martins
Vilma R
VR
Linden
Rafael
R
D000818:Animals; D000831:Animals, Newborn; D000841:Anisomycin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D007106:Immune Sera; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D010766:Phosphorylation; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D011919:Rats, Inbred Strains; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013873:Thionucleotides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D005136:Eye Proteins; D005419:Flavonoids; D007106:Immune Sera; D010446:Peptide Fragments; D018621:PrPC Proteins; D013873:Thionucleotides; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D000841:Anisomycin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one