X-ray crystallographic fragment screening against the human prion protein

Polydatin is found to be a pharmacologically-significant scaffold that can bind to the rPrPres repertoire and inhibit its conversion to the highly infectious and neurotoxic PrPSc-like form, thus acting like a promising anti-prion drug lead.

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Sensitive protein misfolding cyclic amplification of sporadic Creutzfeldt–Jakob disease prions is strongly seed and substrate dependent

Scientific Reports ◽

10.1038/s41598-021-83630-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maxime Bélondrade ◽

Simon Nicot ◽

Charly Mayran ◽

Lilian Bruyere-Ostells ◽

Florian Almela ◽

...

Keyword(s):

Prion Protein ◽

Protein Misfolding ◽

Protein Misfolding Cyclic Amplification ◽

Bank Voles ◽

Substrate Dependence ◽

Brain Extracts ◽

Jakob Disease ◽

Human Prion Protein

AbstractUnlike variant Creutzfeldt–Jakob disease prions, sporadic Creutzfeldt–Jakob disease prions have been shown to be difficult to amplify in vitro by protein misfolding cyclic amplification (PMCA). We assessed PMCA of pathological prion protein (PrPTSE) from 14 human sCJD brain samples in 3 substrates: 2 from transgenic mice expressing human prion protein (PrP) with either methionine (M) or valine (V) at position 129, and 1 from bank voles. Brain extracts representing the 5 major clinicopathological sCJD subtypes (MM1/MV1, MM2, MV2, VV1, and VV2) all triggered seeded PrPTSE amplification during serial PMCA with strong seed- and substrate-dependence. Remarkably, bank vole PrP substrate allowed the propagation of all sCJD subtypes with preservation of the initial molecular PrPTSE type. In contrast, PMCA in human PrP substrates was accompanied by a PrPTSE molecular shift during heterologous (M/V129) PMCA reactions, with increased permissiveness of V129 PrP substrate to in vitro sCJD prion amplification compared to M129 PrP substrate. Combining PMCA amplification sensitivities with PrPTSE electrophoretic profiles obtained in the different substrates confirmed the classification of 4 distinct major sCJD prion strains (M1, M2, V1, and V2). Finally, the level of sensitivity required to detect VV2 sCJD prions in cerebrospinal fluid was achieved.

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Free energy simulations to understand the effect of Met → Ala mutations at positions 205, 206 and 213 on stability of human prion protein

Biophysical Chemistry ◽

10.1016/j.bpc.2021.106620 ◽

2021 ◽

pp. 106620

Author(s):

Kyung-Hoon Lee ◽

Krzysztof Kuczera

Keyword(s):

Free Energy ◽

Prion Protein ◽

Human Prion Protein ◽

Energy Simulations

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Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

Biomolecular NMR Assignments ◽

10.1007/s12104-021-10005-y ◽

2021 ◽

Vol 15 (1) ◽

pp. 193-196

Author(s):

Máximo Sanz-Hernández ◽

Alfonso De Simone

Keyword(s):

Prion Protein ◽

Nmr Assignments ◽

Chemical Shifts ◽

Prion Diseases ◽

Random Coil ◽

Transmissible Spongiform Encephalopathies ◽

Globular Domain ◽

Structural Elements ◽

Spongiform Encephalopathies ◽

Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

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Presence of subclinical infection in gene-targeted human prion protein transgenic mice exposed to atypical bovine spongiform encephalopathy

Journal of General Virology ◽

10.1099/vir.0.052738-0 ◽

2013 ◽

Vol 94 (12) ◽

pp. 2819-2827 ◽

Cited By ~ 11

Author(s):

Rona Wilson ◽

Karen Dobie ◽

Nora Hunter ◽

Cristina Casalone ◽

Thierry Baron ◽

...

Keyword(s):

Human Health ◽

Bovine Spongiform Encephalopathy ◽

Prion Protein ◽

Disease Transmission ◽

Large Scale ◽

Single Agent ◽

Diagnostic Methods ◽

Transmissible Spongiform Encephalopathies ◽

Spongiform Encephalopathy ◽

Human Prion Protein

The transmission of bovine spongiform encephalopathy (BSE) to humans, leading to variant Creutzfeldt–Jakob disease has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health. Until recently, TSE disease in cattle was thought to be caused by a single agent strain, BSE, also known as classical BSE, or BSE-C. However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. To model the risk to human health, we previously inoculated these two forms of atypical BSE (BASE and BSE-H) into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP) (HuTg) but were unable to detect any signs of TSE pathology in these mice. However, despite the absence of TSE pathology, upon subpassage of some BASE-challenged HuTg mice, a TSE was observed in recipient gene-targeted bovine PrP Tg (Bov6) mice but not in HuTg mice. Disease transmission from apparently healthy individuals indicates the presence of subclinical BASE infection in mice expressing human PrP that cannot be identified by current diagnostic methods. However, due to the lack of transmission to HuTg mice on subpassage, the efficiency of mouse-to-mouse transmission of BASE appears to be low when mice express human rather than bovine PrP.

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