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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...

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Autores principales: Myers, Ryan R., Sanchez-Garcia, Jonatan, Leving, Daniel C., Melvin, Richard G., Fernandez-Funez, Pedro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2022
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.
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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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