Abstract
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 (α 1I3) and, by sequence homology, alpha-2-macroglobulin (α2M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrPC with either α 1I3 or α2M. 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 α2M. Interestingly, α2M 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.
| Original language | English |
|---|---|
| Article number | e5968 |
| Journal | PLoS One |
| Volume | 4 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 18 2009 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Prion protein paralog doppel protein interacts with alpha-2-macroglobulin : A plausible mechanism for doppel-mediated neurodegeneration. / Benvegnù, Stefano; Franciotta, Diego; Sussman, Josh; Bachi, Angela; Zardini, Elisabetta; Torreri, Paola; Govaerts, Cedric; Pizzo, Salvatore; Legname, Giuseppe.
In: PLoS One, Vol. 4, No. 6, e5968, 18.06.2009.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Prion protein paralog doppel protein interacts with alpha-2-macroglobulin
T2 - A plausible mechanism for doppel-mediated neurodegeneration
AU - Benvegnù, Stefano
AU - Franciotta, Diego
AU - Sussman, Josh
AU - Bachi, Angela
AU - Zardini, Elisabetta
AU - Torreri, Paola
AU - Govaerts, Cedric
AU - Pizzo, Salvatore
AU - Legname, Giuseppe
PY - 2009/6/18
Y1 - 2009/6/18
N2 - 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 (α 1I3) and, by sequence homology, alpha-2-macroglobulin (α2M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrPC with either α 1I3 or α2M. 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 α2M. Interestingly, α2M 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.
AB - 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 (α 1I3) and, by sequence homology, alpha-2-macroglobulin (α2M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrPC with either α 1I3 or α2M. 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 α2M. Interestingly, α2M 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.
UR - http://www.scopus.com/inward/record.url?scp=67650105637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650105637&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0005968
DO - 10.1371/journal.pone.0005968
M3 - Article
C2 - 19536284
AN - SCOPUS:67650105637
VL - 4
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 6
M1 - e5968
ER -