scholarly journals Accumulation of cellular prion protein within β‐amyloid oligomer plaques in aged human brains

2021 ◽  
Author(s):  
Reisuke H. Takahashi ◽  
Mayumi Yokotsuka ◽  
Minoru Tobiume ◽  
Yuko Sato ◽  
Hideki Hasegawa ◽  
...  
Keyword(s):  
Prion Protein ◽  
Cellular Prion Protein ◽  
Β Amyloid ◽  
Human Brains ◽  
Amyloid Oligomer

Cellular prion protein modulates β-amyloid deposition in aged APP/PS1 transgenic mice

2013 ◽  
Vol 34 (12) ◽  
pp. 2793-2804 ◽  
Author(s):  
Lara Ordóñez-Gutiérrez ◽  
Juan María Torres ◽  
Rosalina Gavín ◽  
Marta Antón ◽  
Ana Isabel Arroba-Espinosa ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Amyloid Deposition ◽  
Cellular Prion Protein ◽  
Β Amyloid

scholarly journals Pharmacological inactivation of the prion protein by targeting a folding intermediate

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Giovanni Spagnolli ◽  
Tania Massignan ◽  
Andrea Astolfi ◽  
Silvia Biggi ◽  
Marta Rigoli ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Surface Glycoprotein ◽  
Folding Intermediate ◽  
Biological Regulation ◽  
Cell Surface Glycoprotein ◽  
Folding Intermediates ◽  
Protein Levels ◽  
Small Molecule Ligands

AbstractRecent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

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