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Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration

Doppel protein (Dpl) is a paralog of the cellular form of the prion protein (PrP(C)), together sharing common structural and biochemical properties. Unlike PrP(C), which is abundantly expressed throughout the central nervous system (CNS), Dpl protein expression is not detectable in the CNS. Interest...

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Autores principales: Benvegnù, Stefano, Franciotta, Diego, Sussman, Josh, Bachi, Angela, Zardini, Elisabetta, Torreri, Paola, Govaerts, Cedric, Pizzo, Salvatore, Legname, Giuseppe
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693666/
https://www.ncbi.nlm.nih.gov/pubmed/19536284
http://dx.doi.org/10.1371/journal.pone.0005968
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author Benvegnù, Stefano
Franciotta, Diego
Sussman, Josh
Bachi, Angela
Zardini, Elisabetta
Torreri, Paola
Govaerts, Cedric
Pizzo, Salvatore
Legname, Giuseppe
author_facet Benvegnù, Stefano
Franciotta, Diego
Sussman, Josh
Bachi, Angela
Zardini, Elisabetta
Torreri, Paola
Govaerts, Cedric
Pizzo, Salvatore
Legname, Giuseppe
author_sort Benvegnù, Stefano
collection PubMed
description Doppel protein (Dpl) is a paralog of the cellular form of the prion protein (PrP(C)), together sharing common structural and biochemical properties. Unlike PrP(C), 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(1)I(3)) and, by sequence homology, alpha-2-macroglobulin (α(2)M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP(C) with either α(1)I(3) or α(2)M. Nevertheless, enzyme-linked immunosorbent assays and surface plasmon resonance experiments revealed a high affinity binding occurring between PrP(C) 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 α(2)M. Interestingly, α(2)M 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.
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spelling pubmed-26936662009-06-18 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 PLoS One Research Article Doppel protein (Dpl) is a paralog of the cellular form of the prion protein (PrP(C)), together sharing common structural and biochemical properties. Unlike PrP(C), 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(1)I(3)) and, by sequence homology, alpha-2-macroglobulin (α(2)M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP(C) with either α(1)I(3) or α(2)M. Nevertheless, enzyme-linked immunosorbent assays and surface plasmon resonance experiments revealed a high affinity binding occurring between PrP(C) 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 α(2)M. Interestingly, α(2)M 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. Public Library of Science 2009-06-18 /pmc/articles/PMC2693666/ /pubmed/19536284 http://dx.doi.org/10.1371/journal.pone.0005968 Text en Benvegnù et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Benvegnù, Stefano
Franciotta, Diego
Sussman, Josh
Bachi, Angela
Zardini, Elisabetta
Torreri, Paola
Govaerts, Cedric
Pizzo, Salvatore
Legname, Giuseppe
Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
title Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
title_full Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
title_fullStr Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
title_full_unstemmed Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
title_short Prion Protein Paralog Doppel Protein Interacts with Alpha-2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration
title_sort prion protein paralog doppel protein interacts with alpha-2-macroglobulin: a plausible mechanism for doppel-mediated neurodegeneration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693666/
https://www.ncbi.nlm.nih.gov/pubmed/19536284
http://dx.doi.org/10.1371/journal.pone.0005968
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