title: Prion protein paralog doppel protein interacts with alpha-2-macroglobulin: a plausible mechanism for doppel-mediated neurodegeneration.
abstract: 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 (alpha(1)I(3)) and, by sequence homology, alpha-2-macroglobulin (alpha(2)M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP(C) with either alpha(1)I(3) or alpha(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 alpha(2)M. Interestingly, alpha(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.
authors.affiliation: Scuola Internazionale Superiore di Studi Avanzati-International School for Advanced Studies (SISSA-ISAS); Italian Institute of Technology, [corrected] Trieste, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Benvegnù
authors.forename: Diego
authors.initials: D
authors.lastname: Franciotta
authors.forename: Josh
authors.initials: J
authors.lastname: Sussman
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zardini
authors.forename: Paola
authors.initials: P
authors.lastname: Torreri
authors.forename: Cedric
authors.initials: C
authors.lastname: Govaerts
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pizzo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D058851:GPI-Linked Proteins; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D011328:Prions / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D000511:alpha-Macroglobulins / Q000737:chemistry*
chemical_list: D058851:GPI-Linked Proteins; D011328:Prions; C122036:Prnd protein, mouse; D000511:alpha-Macroglobulins