Neuroprotective function of the endogenous prion: a new perspective for spongiform encephalopathies

NEUROPROTECTIVE FUNCTION OF THE ENDOGENOUS PRION: A NEW PERSPECTIVE FOR SPONGIFORM ENCEPHALOPATHIES^*

LUCIANA B. CHIARINI¹, ADRIANA R.O. FREITAS², VILMA R. MARTINS³, RICARDO R. BRENTANI²AND RAFAEL LINDEN¹

¹

²Instituto Ludwig

³Fundação Antonio Prudente, São Paulo, Brazil

Spongiform encephalopathies are attributed to conformational conversion of the GPI-anchored endogenous prion protein (PrPc) into a pathogenic isoform. The relative contribution of either the amyloid deposition of converted protein, or the loss of function of the prion protein, to pathogeny of prion diseases remains to be elucidated. Despite the abundance of PrPc in the central nervous system (CNS), its normal functions are largely unknown. A 16-aminoacid synthetic peptide designed on the basis of complementary hydropathy, has been used to produce an antiserum that recognizes a PrPc-binding 66-kDa protein (Martins VR et al. 1997, Nature Med 3: 1376). Here we show that activation of PrPc by this peptide has an anti-apoptotic effect mediated by cAMP-dependent protein kinase in developing nervous tissue. Histotypical retinal explants are used as a model to study the mechanisms of apoptosis in the developing CNS (Linden R et al. 1999, Prog. Ret Eye Res 18: 133). Explants of the retina of neonatal rats or mice were kept in vitro for 24 h. Inhibition of protein synthesis with anisomycin (ANI, g/ml) induced apoptosis of differentiating cells within the immature neuroblastic layer. The 16 aa. peptide partially prevented apoptosis induced by ANI in explants of the retina from wild-type rats and mice, but not from transgenic PrPc mice. The anti-apoptotic effect of the PrPc-ligand peptide was abolished by pre-incubation of explants with PI-PLC (g/ml, 1 h at C), a procedure that releases GPI-anchored proteins from membranes. The PrPc-binding peptide induces in retinal tissue an increase in both cAMP and in the activity of PKA, and increased activation of Erk. Inhibition of cAMP-dependent protein kinase, but not inhibition of the Erk activation pathway abolished the neuroprotective effect of the prion-binding peptide. The results suggest that binding of the 66-kDa ligand protein activates PrPc, which triggers downstream anti-apoptotic signals through the activation of PKA. Thus the endogenous PrPc protein transduces neuroprotective signals in the developing nervous system. These findings are consistent with the hypothesis that the neurological deficits associated with spongiform encephalopathies may depend on loss of function of the endogenous prion protein, leading to increased neuronal vulnerability. — ( June 27, 2000 ).

Publication Dates

• Publication in this collection
  05 Oct 2000
• Date of issue
  Sept 2000