%0 Journal Article
%T Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
%A Stefano Benvegn¨´
%A Diego Franciotta
%A Josh Sussman
%A Angela Bachi
%A Elisabetta Zardini
%A Paola Torreri
%A Cedric Govaerts
%A Salvatore Pizzo
%A Giuseppe Legname
%J PLOS ONE
%D 2009
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0005968
%X Doppel protein (Dpl) is a paralog of the cellular form of the prion protein (PrPC), together sharing common structural and biochemical properties. Unlike PrPC, which is abundantly expressed throughout the central nervous system (CNS), Dpl protein expression is not detectable in the CNS. Interestingly, its ectopic expression in the brain elicits neurodegeneration in transgenic mice. Here, by combining native isoelectric focusing plus non-denaturing polyacrylamide gel electrophoresis and mass spectrometry analysis, we identified two Dpl binding partners: rat alpha-1-inhibitor-3 (¦Á1I3) and, by sequence homology, alpha-2-macroglobulin (¦Á2M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrPC with either ¦Á1I3 or ¦Á2M. Nevertheless, enzyme-linked immunosorbent assays and surface plasmon resonance experiments revealed a high affinity binding occurring between PrPC and Dpl. In light of these findings, we suggest a mechanism for Dpl-induced neurodegeneration in mice expressing Dpl ectopically in the brain, linked to a withdrawal of natural inhibitors of metalloproteinase such as ¦Á2M. Interestingly, ¦Á2M has been proven to be a susceptibility factor in Alzheimer's disease, and as our findings imply, it may also play a relevant role in other neurodegenerative disorders, including prion diseases.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0005968