Apoptosis and Prion Proteins

Science's STKE  23 Oct 2001:
Vol. 2001, Issue 105, pp. tw397
DOI: 10.1126/stke.2001.105.tw397

Prions are best known for their role in neurodegenerative diseases, including spongiform encephalopathy. Two new reports propose mechanisms by which prion proteins may influence neuronal apoptosis. Bounhar et al. suggest that one role for native prion protein (PrP) is to protect neurons from apoptosis mediated by Bax-dependent processes. Della-Bianca et al. suggest a different mechanism in which the prion peptide fragment PrP106-126 may exert its neurotoxic effect by stimulating apoptosis through activation of the death domain-containing neurotrophin receptor p75NTR. Bounhar et al. showed that injection of neurons with both the proapoptotic protein Bax and PrP protected the neurons from apoptosis. Conversely, depletion of endogenous PrP with antisense RNA enhanced Bax-mediated cell death. Furthermore, deletion of the Bcl-2 homology domain (BH2)-like repeats in PrP produced a form of the protein that was not protective, suggesting that PrP may mediate its effects by interaction with proapoptotic proteins through this domain. Although, the majority of native PrP is anchored to the plasma membrane through a glycophosphatidyl inositol modification, this posttranslational modification was not required for antiapoptotic effect; however, maturation and complete trafficking through the secretory pathway were required for neuroprotection. Finally, the ability of PrP to be antiapoptotic was partially lost in the mutant form associated with familial atypical spongiform encephalopathy and completely abolished in the mutant form associated with fatal familial insomnia. Thus, the normal PrP may be an inhibitor of apoptosis, which may explain some of the neuroprotective effects of endogenous PrP in vivo models of prion disease. Della-Bianca et al. studied the effects of the prion fragment PrP106-126 (which is known to mimic the structure and biological effects of the Scrapie form of prion protein) on cultured neuroblastoma cell lines transfected with wild-type or mutants of p75NTR. PrP106-126 exhibited saturable high-affinity binding to cells expressing p75NTR, but not to mutants lacking the extracellular domain. Furthermore, in cells expressing p75NTR, PrP106-126 induced cell death in a process that could be inhibited with caspase inhibitors and that required the intracellular domain of the receptor. Thus, p75NTR may be a receptor for PrP106-126 that contributes to the neurotoxic effects of this peptide. If the Scrapie prion protein shares this property of the PrP106-126, activation of p75NTR might contribute to toxicity of the protein.

Y. Bounhar, Y. Zhang, C. G. Goodyer, A. LeBlanc, Prion protein protects human nuerons against Bax-mediated apoptosis. J. Biol. Chem. 276, 39145-39149 (2001). [Abstract] [Full Text]

V. Della-Bianca, F. Rossi, U. Armato, I. Dal-Pra, C. Costantini, G. Perini, V. Politi, G. Della Valle, Neurotrophin p75 receptor is involved in neuronal damage by prion peptide-(106-126). J. Biol. Chem. 276, 38929-38933 (2001). [Abstract] [Full Text]