NMR Structural Studies of Human Cellular Prion Proteins

Biljan, Ivana; Ilc, Gregor; Giachin, Gabriele; Legname, Giuseppe; Plavec, Janez

doi:10.2174/15680266113136660169

Cited by 13 publications

(9 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Traditional homonuclear through-bond correlation methods via correlation spectroscopy (COSY/TOSCY) combined with throughspace correlation via nuclear Overhauser effect spectroscopy/rotating frame nuclear Overhauser effect spectroscopy (NOESY/ROESY) were limiting to studying IDPs of short chain lengths (Felli & Pierattelli, 2015), but now heteronuclear correlation experiments with 13 C and 15 N isotopic labels are routinely used for IDPs (Wiedemann et al, 2015). For example, 2D or 3D Heteronuclear Single/Multiple Quantum Coherence (HSQC/HMQC) experiments have provided NMR parameters for amyloidogenic IDPs, Aβ40 and Aβ42 (Rosenman, Connors, Chen, Wang, & Garcia, 2013;Yan, McCallum, & Wang, 2008), human PrP (Biljan, Ilc, Giachin, Legname, & Plavec, 2013), Tau (Lippens et al, 2016), and α-syn (Bai, Cheng, Liu, & Li, 2016). Two recent studies on macrocyclic β-sheet peptides, using a single 15 N isotopic probe by 1 H-15 N HSQC and 15 N-Edited NOESY experiments, highlights the predisposition of peptides containing the aggregation-prone central hydrophobic residues 17-23 and C-terminal residues 30-36 of Aβ to assemble and co-assemble largely into heterotetramers (and homotetramers).…”

Section: Structural and Mechanistic Insights Gleaned From Experiments: Comparison With Simulationsmentioning

confidence: 99%

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Bhattacharya

Thompson

2018

WIREs Comput Mol Sci

View full text Add to dashboard Cite

Neurodegenerative amyloidogenesis begins with the aggregation of intrinsically disordered proteins (IDPs), which is the first step in a cascade of assembly events that can lead to insoluble fibrous deposits in brain tissue. IDP conformations that promote formation of toxic oligomers remain poorly understood, and are the most fundamental target of putative treatments for neurodegenerative disease. Rapid advances in theory, simulation and experimental methods, hold the promise of reversing protein aggregation by identifying and developing inhibitors of the transient amyloidogenic IDP conformations. To make meaningful progress it is important to appreciate the benefits and limitations of the latest developments in computational methods of conformational and ensemble modeling, and their integration and validation with experiments. Integrated studies are beginning to provide significant conceptual and mechanistic insights, including identification of the properties of amyloidogenic IDPs in their free, unbound form. At the same time, contradicting viewpoints have emerged concerning convergence of IDP ensemble signatures and properties from parallel studies, and there also remains a pressing need to develop physical models that can deliver reliable predictions across different IDP families. Focussing on the four most common amyloidogenic IDPs of Amyloid β, Tau, α‐synuclein and Prions, improvements are proposed for next‐generation models and experiments that can potentially identify drug treatments for neurodegenerative disease via incorporation of the extended cellular environment. This article is categorized under: Molecular and Statistical Mechanics > Molecular Mechanics Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Molecular Structures

show abstract

Section: Structural and Mechanistic Insights Gleaned From Experiments: Comparison With Simulationsmentioning

confidence: 99%

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Bhattacharya

Thompson

2018

WIREs Comput Mol Sci

View full text Add to dashboard Cite

show abstract

“…The threonine to serine substitution studied here is also conservative, as both these amino acids are uncharged, polar, and of similar size; serine being slightly smaller due to the substitution of a proton for the methyl group found in the threonine side chain. Furthermore, X-ray and nuclear magnetic resonance studies of recombinant PrP C ( Antonyuk et al., 2009 , Biljan et al., 2013 ) show that T201 is situated at the start of helix 3 of the PrP, with its side chain predominantly solvent exposed rather than within the protein core; thus, unlikely to destabilize PrP C ( Fig. 3 ).…”

Section: Resultsmentioning

confidence: 99%

Evaluating the causality of novel sequence variants in the prion protein gene by example

Mok

Koriath²,

Jaunmuktane

et al. 2018

Neurobiology of Aging

View full text Add to dashboard Cite

The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10 weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease–specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP.

show abstract

“…PrP is a highly evolutionarily conserved cellular protein comprised of three α-helices and an antiparallel β-sheet 8 9. Its exact function remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as conversion disorder

Jiang¹,

Longardner

Dickson

et al. 2019

BMJ Case Rep

View full text Add to dashboard Cite

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare cause of genetic prion disease. Overlapping neurological, cognitive and psychiatric symptoms make GSS difficult to diagnose based on clinical features alone. We present a 40-year-old man without relevant medical or family history who developed progressive neurocognitive and behavioural symptoms over 3 years. Initial extensive diagnostic workup of his variable motor symptoms was unrevealing and he was diagnosed with conversion disorder. This diagnosis persisted for over 2 years, despite progressive neurocognitive symptoms. He eventually developed dementia and severe neurological impairment. Repeat brain MRI revealed generalised cortical volume loss, establishing the diagnosis of a rapidly progressive neurodegenerative process. He ultimately died from aspiration pneumonia at age 43. Postmortem neuropathological examination showed widespread multicentric prion protein amyloid plaques characteristic of GSS. Ultimately, genetic testing of brain tissue revealed a heterozygous A117V variant in the PNRP gene, confirming the diagnosis.

show abstract

NMR Structural Studies of Human Cellular Prion Proteins

Cited by 13 publications

References 0 publications

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Revisiting the earliest signatures of amyloidogenesis: Roadmaps emerging from computational modeling and experiment

Evaluating the causality of novel sequence variants in the prion protein gene by example

Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as conversion disorder

Contact Info

Product

Resources

About