دورية أكاديمية
New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein
| العنوان: | New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein |
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| المؤلفون: | Ryan R. Myers, Jonatan Sanchez-Garcia, Daniel C. Leving, Richard G. Melvin, Pedro Fernandez-Funez |
| المصدر: | Disease Models & Mechanisms, Vol 15, Iss 4 (2022) |
| بيانات النشر: | The Company of Biologists, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Pathology |
| مصطلحات موضوعية: | prion diseases, prion protein, drosophila, transgenic models, protective amino acids, heat shock proteins, unfolded protein response, perk, atf4 suppressors, Medicine, Pathology, RB1-214 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1754-8403 1754-8411 |
| Relation: | http://dmm.biologists.org/content/15/4/dmm049184; https://doaj.org/toc/1754-8403; https://doaj.org/toc/1754-8411 |
| DOI: | 10.1242/dmm.049184 |
| URL الوصول: | https://doaj.org/article/65496c7ab5c241ebb2ff9ae3768816d3 |
| رقم الأكسشن: | edsdoj.65496c7ab5c241ebb2ff9ae3768816d3 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17548403 17548411 |
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| DOI: | 10.1242/dmm.049184 |