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New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein
Misfolding of the prion protein (PrP) is responsible for devastating neurological disorders in humans and other mammals. An unresolved problem in the field is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The var...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9093039/ https://www.ncbi.nlm.nih.gov/pubmed/35142350 http://dx.doi.org/10.1242/dmm.049184 |
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author | Myers, Ryan R. Sanchez-Garcia, Jonatan Leving, Daniel C. Melvin, Richard G. Fernandez-Funez, Pedro |
author_facet | Myers, Ryan R. Sanchez-Garcia, Jonatan Leving, Daniel C. Melvin, Richard G. Fernandez-Funez, Pedro |
author_sort | Myers, Ryan R. |
collection | PubMed |
description | Misfolding of the prion protein (PrP) is responsible for devastating neurological disorders in humans and other mammals. An unresolved problem in the field is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases is a natural resource that can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with new, robust phenotypes in brain neurons and the eye. By using comparable attP2 insertions, we demonstrated the heightened toxicity of human PrP compared to rodent PrP along with a specific interaction with the amyloid-β peptide. By using this new model, we started to uncover the intrinsic (sequence/structure) and extrinsic (interactions) factors regulating PrP toxicity. We described PERK (officially known as EIF2AK3 in humans) and activating transcription factor 4 (ATF4) as key in the cellular mechanism mediating the toxicity of human PrP and uncover a key new protective activity for 4E-BP (officially known as Thor in Drosophila and EIF4EBP2 in humans), an ATF4 transcriptional target. Lastly, mutations in human PrP (N159D, D167S, N174S) showed partial protective activity, revealing its high propensity to misfold into toxic conformations. |
format | Online Article Text |
id | pubmed-9093039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-90930392022-05-12 New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein Myers, Ryan R. Sanchez-Garcia, Jonatan Leving, Daniel C. Melvin, Richard G. Fernandez-Funez, Pedro Dis Model Mech Research Article Misfolding of the prion protein (PrP) is responsible for devastating neurological disorders in humans and other mammals. An unresolved problem in the field is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases is a natural resource that can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with new, robust phenotypes in brain neurons and the eye. By using comparable attP2 insertions, we demonstrated the heightened toxicity of human PrP compared to rodent PrP along with a specific interaction with the amyloid-β peptide. By using this new model, we started to uncover the intrinsic (sequence/structure) and extrinsic (interactions) factors regulating PrP toxicity. We described PERK (officially known as EIF2AK3 in humans) and activating transcription factor 4 (ATF4) as key in the cellular mechanism mediating the toxicity of human PrP and uncover a key new protective activity for 4E-BP (officially known as Thor in Drosophila and EIF4EBP2 in humans), an ATF4 transcriptional target. Lastly, mutations in human PrP (N159D, D167S, N174S) showed partial protective activity, revealing its high propensity to misfold into toxic conformations. The Company of Biologists Ltd 2022-05-04 /pmc/articles/PMC9093039/ /pubmed/35142350 http://dx.doi.org/10.1242/dmm.049184 Text en © 2022. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Myers, Ryan R. Sanchez-Garcia, Jonatan Leving, Daniel C. Melvin, Richard G. Fernandez-Funez, Pedro New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
title | New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
title_full | New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
title_fullStr | New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
title_full_unstemmed | New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
title_short | New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
title_sort | new drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9093039/ https://www.ncbi.nlm.nih.gov/pubmed/35142350 http://dx.doi.org/10.1242/dmm.049184 |
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