ArticleDisease models & mechanisms2022
New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein.
Article in Disease models & mechanisms, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed, 7 citations in OpenAlex.
- Prion Protein Codon Implicated in Resistance in Dogs Detected in Non-Domesticated Members of Mammalia.Animals : an open access journal from MDPI · 2026Article
- Functional assays inGenome research · 2025Review
- Conformational dynamics as an intrinsic determinant of prion protein misfolding and neurotoxicity.Neural regeneration research · 2024Article
- Review
- Intrinsic determinants of prion protein neurotoxicity inFrontiers in molecular neuroscience · 2023Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
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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Registered trials
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