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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2020
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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. |
format | Online Article Text |
id | pubmed-7253391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
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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