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Intrinsic determinants of prion protein neurotoxicity in Drosophila: from sequence to (dys)function

Summary

Prion diseases are deadly brain conditions caused by misfolded proteins. This study used computer simulations and fruit fly experiments to understand how tiny changes in prion protein structure affect its ability to cause disease. Researchers found that proteins with flexible loops are more toxic, while those with more rigid structures cause less damage, suggesting new ways to develop treatments by stabilizing the protein’s structure.

Background

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the prion protein (PrP). A 3D subdomain comprising the β2-α2 loop and helix 3 (CT3DD) shows high sequence variability among animals and is proposed as a key regulator of PrP misfolding. Understanding the intrinsic determinants governing PrP dynamics is critical for understanding disease susceptibility.

Objective

To identify how amino acid sequence variations in PrP affect conformational dynamics and neurotoxicity. The study combines molecular dynamics (MD) simulations with in vivo functional studies in Drosophila to assess the impact of candidate substitutions on PrP misfolding propensity and toxicity.

Results

MD simulations revealed that human PrP-WT exhibits high conformational polymorphism in the β2-α2 loop with multiple β-turn conformations, while the Y225A substitution strongly favors a 3₁₀-turn conformation. Y225A showed significantly lower neurotoxicity in flies, reduced neurodegeneration in mushroom body neurons, and lower propensity for aggregation compared to wild-type PrP.

Conclusion

Conformational dynamics of the CT3DD, particularly the β2-α2 loop flexibility, correlates with PrP toxicity and misfolding propensity. The authors propose a new paradigm incorporating sequence→structure→dynamics→function analysis and suggest that stabilizing the β2-α2 loop through specific amino acid substitutions may reduce PrP toxicity.
  • Published in:Frontiers in Molecular Neuroscience,
  • Study Type:Research Article, Computational and Experimental Study,
  • Source: PMC10461008, PMID: 37645703, doi: 10.3389/fnmol.2023.1231079
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