Mastrangelo P, Serpell L, Dafforn T, Lesk A, Fraser P, Westaway D.
A cluster of familial Creutzfeldt-Jakob disease mutations recapitulate conserved residues in Doppel: a case of molecular mimicry?.
FEBS Lett. 2002 Dec 4;532(1-2):21-6.
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23284 Comment by Andrea LeBlanc:
This interesting paper shows that quite a few of the disease-associated human prion mutations actually switch to the normal Doppel sequence. The doppel (i.e., “doppelgaenger”) gene is downstream of the PrP gene. Its protein resembles amino-terminally truncated PrP and interacts with PrP.) Doppel overexpression is neurotoxic. Therefore, the switch of PrP into a Doppel-like protein could indicate that Doppel and mutant PrP are neurotoxic through a similar mechanism. However, it remains to be seen if these mutant PrPs are neurotoxic or not.
Our work has focused on the function of normal prion protein in primary human neurons. I suspected a function for prion protein in cell death or cell survival because of some similarity between the BH2 domain of Bcl-2 proteins and the octapeptide repeat of prion protein. While we now know that PrP is not a member of the Bcl-2 family of proteins, it is, however, a strong neuroprotective agent against Bax-mediated cell death. We have tested a few mutants, and PrP D178N completely loses the neuroprotective function while T183A partially loses it. Neither of these mutations reiterates the Doppel amino acids and neither is toxic when expressed in human neurons for at least 16 days. More mutations are being tested in my laboratory, and we are anxious to see if any of these, especially the ones shown by Mastrangelo et al., will induce toxicity in human neurons. (For review, see Roucou et al., 2004.)