α<sub>2</sub>-Macroglobulin is a potential facilitator of prion protein transformation

Adler, Victor; Davidowitz, Eliot J.; Tamburi, Patricia; Rojas, Pedro Augusto Díaz; Grossman, Abraham

doi:10.1080/13506120600960452

Cited by 8 publications

(5 citation statements)

References 31 publications

(54 reference statements)

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“…This finding raises the question whether a possible interaction of PrP C with LRP could have a key role in the conversion of PrP C into PrP Sc . Interestingly, α 2 M was found to facilitate, at least in vitro , PrP C –PrP Sc conversion [51]. In light of our findings, albeit α 2 M was not found to directly interact with PrP C , it cannot be ruled out that α 2 M activity could play a role also in prion diseases and other neurodegenerative disorders in addition to AD.…”

Section: Discussioncontrasting

confidence: 48%

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

et al. 2009

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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 (α1I3) and, by sequence homology, alpha-2-macroglobulin (α2M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrPC with either α1I3 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.

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Section: Discussioncontrasting

confidence: 48%

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

et al. 2009

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“…This finding raises the question whether a possible interaction of PrP C with LRP could have a key role in the conversion of PrP C into PrP Sc . Interestingly, a 2 M was found to facilitate, at least in vitro, PrP C -PrP Sc conversion [51]. In light of our findings, albeit a 2 M was not found to directly interact with PrP C , it cannot be ruled out that a 2 M activity could play a role also in prion diseases and other neurodegenerative disorders in addition to AD.…”

Section: Discussionmentioning

confidence: 49%

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

Benvegnù¹,

Franciotta²,

Sussman³

et al. 2009

PLoS ONE

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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 (a 1 I 3 ) and, by sequence homology, alpha-2-macroglobulin (a 2 M), two known plasma metalloproteinase inhibitors. Biochemical investigations excluded the direct interaction of PrP C with either a 1 I 3 or a 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 a 2 M. Interestingly, a 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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“…A2M polymorphisms have been suggested as a genetic risk factor for Alzheimer’s disease [ 110 , 111 , 112 , 113 , 114 ], although this has been disputed [ 115 , 116 ]. α2m has also been reported to bind to other pathogenic proteins, including prion protein (the causative agent in spongiform encephalopathy) [ 117 ] and α-synuclein (which aggregates in the neurons of Parkinson’s disease patients) [ 118 ].…”

Section: Extracellular Chaperones (Ecs) Implicated In Complement Regu...mentioning

confidence: 99%

The Emerging Roles of Extracellular Chaperones in Complement Regulation

Geraghty

Satapathy

Wilson

2022

Cells

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The immune system is essential to protect organisms from internal and external threats. The rapidly acting, non-specific innate immune system includes complement, which initiates an inflammatory cascade and can form pores in the membranes of target cells to induce cell lysis. Regulation of protein homeostasis (proteostasis) is essential for normal cellular and organismal function, and has been implicated in processes controlling immunity and infection. Chaperones are key players in maintaining proteostasis in both the intra- and extracellular environments. Whilst intracellular proteostasis is well-characterised, the role of constitutively secreted extracellular chaperones (ECs) is less well understood. ECs may interact with invading pathogens, and elements of the subsequent immune response, including the complement pathway. Both ECs and complement can influence the progression of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, as well as other diseases including kidney diseases and diabetes. This review will examine known and recently discovered ECs, and their roles in immunity, with a specific focus on the complement pathway.

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α₂-Macroglobulin is a potential facilitator of prion protein transformation

Cited by 8 publications

References 31 publications

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

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

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

The Emerging Roles of Extracellular Chaperones in Complement Regulation

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α2-Macroglobulin is a potential facilitator of prion protein transformation

Cited by 8 publications

References 31 publications

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

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

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

The Emerging Roles of Extracellular Chaperones in Complement Regulation

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α₂-Macroglobulin is a potential facilitator of prion protein transformation