New Drosophila models to uncover the intrinsic and extrinsic factors that mediate the toxicity of the human prion protein

Ryan R Myers, Jonatan Sanchez-Garcia, Daniel C. Leving, Richard G Melvin, Pedro Fernandez-Funez

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Article numberdmm049184
JournalDMM Disease Models and Mechanisms
Volume15
Issue number4
DOIs
StatePublished - Apr 2022

Bibliographical note

Funding Information:
RSCB Protein Data Bank and ClustalW2, for free data and software; and the University of Minnesota Information Technology Support Services for institutional copies of PyMOL, Adobe 2021 products and JMP Pro 16. This work was supported by the resources and staff at the University of Minnesota Imaging Centers (SCR_020997). Gail Celio assisted with sample preparation and TEM imaging of the eyes. Confocal and SEM images were collected at the Research Instrumentation Laboratory (UMN-UMD).

Funding Information:
This work was supported by the National Institutes of Health (NIH) (grant number: 7R21NS096627-02) and the Winston and Maxine Wallin Neuroscience Discovery Fund award (grant number: CON000000083928) to P.F.-F.

Funding Information:
We thank the Bloomington Drosophila Stock Center (NIH P40OD018537), the Vienna Drosophila Stock Center, and FlyORF, HD Ryoo for transgenic flies; the RSCB Protein Data Bank and ClustalW2, for free data and software; and the University of Minnesota Information Technology Support Services for institutional copies of PyMOL, Adobe 2021 products and JMP Pro 16. This work was supported by the resources and staff at the University of Minnesota Imaging Centers (SCR_020997). Gail Celio assisted with sample preparation and TEM imaging of the eyes. Confocal and SEM images were collected at the Research Instrumentation Laboratory (UMN-UMD). This work was supported by the National Institutes of Health (NIH) (grant number: 7R21NS096627-02) and the Winston and Maxine Wallin Neuroscience Discovery Fund award (grant number: CON000000083928) to P.F.-F.

Publisher Copyright:
© 2022. Published by The Company of Biologists Ltd

Keywords

  • ATF4 suppressors
  • Drosophila
  • Heat shock proteins
  • PERK
  • Prion diseases
  • Prion protein
  • Protective amino acids
  • Transgenic models
  • Unfolded protein response

PubMed: MeSH publication types

  • Journal Article

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