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Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation

The structurally disordered N-terminal half of the prion protein (PrP(C)) is constitutively released into the extracellular space by an endogenous proteolytic cleavage event. Once liberated, this N1 fragment acts neuroprotective in ischemic conditions and interferes with toxic peptides associated wi...

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Autores principales: Mohammadi, Behnam, Linsenmeier, Luise, Shafiq, Mohsin, Puig, Berta, Galliciotti, Giovanna, Giudici, Camilla, Willem, Michael, Eden, Thomas, Koch-Nolte, Friedrich, Lin, Yu-Hsuan, Tatzelt, Jörg, Glatzel, Markus, Altmeppen, Hermann C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253391/
https://www.ncbi.nlm.nih.gov/pubmed/32367491
http://dx.doi.org/10.1007/s12035-020-01917-2
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author Mohammadi, Behnam
Linsenmeier, Luise
Shafiq, Mohsin
Puig, Berta
Galliciotti, Giovanna
Giudici, Camilla
Willem, Michael
Eden, Thomas
Koch-Nolte, Friedrich
Lin, Yu-Hsuan
Tatzelt, Jörg
Glatzel, Markus
Altmeppen, Hermann C.
author_facet Mohammadi, Behnam
Linsenmeier, Luise
Shafiq, Mohsin
Puig, Berta
Galliciotti, Giovanna
Giudici, Camilla
Willem, Michael
Eden, Thomas
Koch-Nolte, Friedrich
Lin, Yu-Hsuan
Tatzelt, Jörg
Glatzel, Markus
Altmeppen, Hermann C.
author_sort Mohammadi, Behnam
collection PubMed
description The structurally disordered N-terminal half of the prion protein (PrP(C)) is constitutively released into the extracellular space by an endogenous proteolytic cleavage event. Once liberated, this N1 fragment acts neuroprotective in ischemic conditions and interferes with toxic peptides associated with neurodegenerative diseases, such as amyloid-beta (Aβ) in Alzheimer’s disease. Since analog protective effects of N1 in prion diseases, such as Creutzfeldt-Jakob disease, have not been studied, and given that the protease releasing N1 has not been identified to date, we have generated and characterized transgenic mice overexpressing N1 (TgN1). Upon intracerebral inoculation of TgN1 mice with prions, no protective effects were observed at the levels of survival, clinical course, neuropathological, or molecular assessment. Likewise, primary neurons of these mice did not show protection against Aβ toxicity. Our biochemical and morphological analyses revealed that this lack of protective effects is seemingly due to an impaired ER translocation of the disordered N1 resulting in its cytosolic retention with an uncleaved signal peptide. Thus, TgN1 mice represent the first animal model to prove the inefficient ER translocation of intrinsically disordered domains (IDD). In contrast to earlier studies, our data challenge roles of cytoplasmic N1 as a cell penetrating peptide or as a potent “anti-prion” agent. Lastly, our study highlights both the importance of structured domains in the nascent chain for proteins to be translocated and aspects to be considered when devising novel N1-based therapeutic approaches against neurodegenerative diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-020-01917-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-72533912020-06-05 Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation Mohammadi, Behnam Linsenmeier, Luise Shafiq, Mohsin Puig, Berta Galliciotti, Giovanna Giudici, Camilla Willem, Michael Eden, Thomas Koch-Nolte, Friedrich Lin, Yu-Hsuan Tatzelt, Jörg Glatzel, Markus Altmeppen, Hermann C. Mol Neurobiol Article The structurally disordered N-terminal half of the prion protein (PrP(C)) is constitutively released into the extracellular space by an endogenous proteolytic cleavage event. Once liberated, this N1 fragment acts neuroprotective in ischemic conditions and interferes with toxic peptides associated with neurodegenerative diseases, such as amyloid-beta (Aβ) in Alzheimer’s disease. Since analog protective effects of N1 in prion diseases, such as Creutzfeldt-Jakob disease, have not been studied, and given that the protease releasing N1 has not been identified to date, we have generated and characterized transgenic mice overexpressing N1 (TgN1). Upon intracerebral inoculation of TgN1 mice with prions, no protective effects were observed at the levels of survival, clinical course, neuropathological, or molecular assessment. Likewise, primary neurons of these mice did not show protection against Aβ toxicity. Our biochemical and morphological analyses revealed that this lack of protective effects is seemingly due to an impaired ER translocation of the disordered N1 resulting in its cytosolic retention with an uncleaved signal peptide. Thus, TgN1 mice represent the first animal model to prove the inefficient ER translocation of intrinsically disordered domains (IDD). In contrast to earlier studies, our data challenge roles of cytoplasmic N1 as a cell penetrating peptide or as a potent “anti-prion” agent. Lastly, our study highlights both the importance of structured domains in the nascent chain for proteins to be translocated and aspects to be considered when devising novel N1-based therapeutic approaches against neurodegenerative diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12035-020-01917-2) contains supplementary material, which is available to authorized users. Springer US 2020-05-04 2020 /pmc/articles/PMC7253391/ /pubmed/32367491 http://dx.doi.org/10.1007/s12035-020-01917-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mohammadi, Behnam
Linsenmeier, Luise
Shafiq, Mohsin
Puig, Berta
Galliciotti, Giovanna
Giudici, Camilla
Willem, Michael
Eden, Thomas
Koch-Nolte, Friedrich
Lin, Yu-Hsuan
Tatzelt, Jörg
Glatzel, Markus
Altmeppen, Hermann C.
Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation
title Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation
title_full Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation
title_fullStr Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation
title_full_unstemmed Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation
title_short Transgenic Overexpression of the Disordered Prion Protein N1 Fragment in Mice Does Not Protect Against Neurodegenerative Diseases Due to Impaired ER Translocation
title_sort transgenic overexpression of the disordered prion protein n1 fragment in mice does not protect against neurodegenerative diseases due to impaired er translocation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253391/
https://www.ncbi.nlm.nih.gov/pubmed/32367491
http://dx.doi.org/10.1007/s12035-020-01917-2
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