NMDA receptor misalignment in iPSC-derived neurons from a multi-generational family with inherited Creutzfeldt-Jakob disease DOI Open Access
Nhat T. T. Le, Robert C.C. Mercer,

Aldana D. Gojanovich

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Май 23, 2022

Summary The most common subtype of genetic prion disease is caused by the E200K mutation protein. We have obtained samples from 22 members a multi-generational Israeli family harboring this mutation, and generated library induced pluripotent stem cells (iPSCs) representing nine carriers four non-carriers. Whole-exome sequencing was performed on all individuals. A comparison neurons derived iPSCs to those non-carriers revealed presence several disease-relevant phenotypes. Neurons were found contain thioflavin S-positive accumulations PrP in their cell bodies. In addition, these displayed disruptions NMDA receptor/PSD95 co-localization at postsynaptic sites. Our study shows that iPSC-derived neurons, which express physiologically relevant levels mutant human neuronal context, can model certain aspects disease, offering powerful platform for investigating pathological mechanisms testing potential therapeutics.

Язык: Английский

Creutzfeldt–Jakob disease and other prion diseases DOI
Inga Zerr, Anna Ladogana, Simon Mead

и другие.

Nature Reviews Disease Primers, Год журнала: 2024, Номер 10(1)

Опубликована: Фев. 29, 2024

Язык: Английский

Процитировано

21
Oxidative Stress and Mitochondrial Impairment: Key Drivers in Neurodegenerative Disorders DOI

Pei Wen,

Zhixin Sun,

Fengting Gou

и другие.

Ageing Research Reviews, Год журнала: 2025, Номер unknown, С. 102667 - 102667

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
What Are the Roles of Cellular Prion Protein in Normal and Pathologic Conditions? DOI
Eduardo E. Benarroch

Neurology, Год журнала: 2024, Номер 102(7)

Опубликована: Март 14, 2024

Язык: Английский

Процитировано

2
The importance of prion research DOI
Shehab Eid, Seojin Lee, Claire Verkuyl

и другие.

Biochemistry and Cell Biology, Год журнала: 2024, Номер 102(6), С. 448 - 471

Опубликована: Июль 12, 2024

Over the past four decades, prion diseases have received considerable research attention owing to their potential be transmitted within and across species as well consequences for human animal health. The unprecedented nature of prions has led discovery a paradigm templated protein misfolding that underlies diverse range both disease-related normal biological processes. Indeed, “prion-like” propagation aggregates is now recognized common underlying disease mechanism in neurodegenerative disorders such Alzheimer's Parkinson's disease, principle development novel diagnostic therapeutic strategies these illnesses. Despite advances, into fundamental biology declined, likely due rarity absence an acute health crisis. Given translational influence, continued on etiology, pathogenesis, transmission should remain priority. In this review, we highlight several important “unsolved mysteries” field how solving them may crucial effective therapeutics, preventing future outbreaks understanding pathobiology more disorders.

Язык: Английский

Процитировано

2
Human prion diseases - state of the art 2023 DOI
Egon Kurča, Štefan Sivák,

Pavol Skáčik

и другие.

Neurologie pro praxi, Год журнала: 2024, Номер 25(1), С. 19 - 25

Опубликована: Март 6, 2024

Humánne priónové ochorenia (PO) predstavujú osobitnú skupinu letálnych neurodegeneratívnych ochorení. Hlavným zástupcom je Creutzfeldtova­‑Jakobova choroba (CJD), ktorá prototypom rýchlo sa rozvíjajúcej demencie. Článok pojednáva o klinických a genetických korelátoch CJD s dôrazom na identifikáciu foriem vrátane genetického poradenstva. Pri získaných PO zaujímavým faktom ukončenie výskytu kuru nového variantu CJD, keď cielené epidemiologické opatrenia viedli k prerušeniu vzorca prenosu patologického priónového proteínu (PrPSc). Zo zriedkavých rozoberáme vzácne diagnostikovanú Gerstmannovu­‑Sträusslerovu­‑Scheinkerovu chorobu (GSS), ako aj unikátnu fatálnu familiárnu insomniu (FFI). Cieľom príspevku podať aktuálne informácie humánnych PO.

Процитировано

1
Sigma Receptor Ligands Are Potent Antiprion Compounds that Act Independently of Sigma Receptor Binding DOI
Robert C.C. Mercer, Nhat T. T. Le,

Douglas G. Fraser

и другие.

ACS Chemical Neuroscience, Год журнала: 2024, Номер 15(11), С. 2265 - 2282

Опубликована: Май 14, 2024

Prion diseases are invariably fatal neurodegenerative of humans and other animals for which there no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class anti-prion compounds. While working to identify the molecular target(s) these molecules, we unexpectedly discovered ten antiprion compounds based on their known ability bind sigma receptors, σ1R σ2R, currently being tested therapeutic or diagnostic targets cancer neuropsychiatric disorders. Surprisingly, however, knockout respective genes encoding σ2R (Sigmar1 Tmem97) in prion-infected N2a cells did not alter activity compounds, demonstrating that receptors direct responsible effects ligands. Further investigation most potent molecules established they efficacious against multiple prion strains protect downstream prion-mediated synaptotoxicity. precise details mechanism action remain be determined, present forms basis further preclinical studies. Given utility several including rimcazole haloperidol conditions, (+)-pentazocine neuropathic pain, ongoing clinical trials SA 4503 ANAVEX2-73 ischemic stroke Alzheimer's disease, respectively, this has immediate implications human disease.

Язык: Английский

Процитировано

1
Genome wide association study of clinical duration and age at onset of sporadic CJD DOI Creative Commons
Holger Hummerich,

Helen E. Speedy,

Tracy Campbell

и другие.

PLoS ONE, Год журнала: 2024, Номер 19(7), С. e0304528 - e0304528

Опубликована: Июль 26, 2024

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research therapeutics. We assembled array genotyped sCJD cases diagnosed life autopsy. Clinical (median:4, interquartile range (IQR):2.5–9 (months)) was available 3,773 (median:67, IQR:61–73 (years)) 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved significance the phenotype; all which located chromosome 20 (top SNP rs1799990, pvalue = 3.45x10 -36 , beta 0.34 an additive model; 9.92x10 -67 0.84 a heterozygous model). Fine mapping, conditional expression suggests that well-known non-synonymous variant codon 129 obvious outstanding determinant duration. Pathway suggestive loci described. No significant found, but HS6ST3 gene (pvalue 1.93 x 10 −6 ) gene-based test. found no evidence genetic correlation between case-control (disease risk factors) case-only (determinants phenotypes) studies. Relative other variants, PRNP by far modifier CJD survival suggesting only modest rare effects loci.

Язык: Английский

Процитировано

1
Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease DOI Creative Commons

Aldana D. Gojanovich,

Nhat T. T. Le, Robert C.C. Mercer

и другие.

Stem Cell Reports, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

Процитировано

1
New developments in prion disease research DOI Open Access
Sabine Gilch, Hermann Schätzl

Cell and Tissue Research, Год журнала: 2023, Номер 392(1), С. 1 - 5

Опубликована: Март 15, 2023

Язык: Английский

Процитировано

2
Protein-lipid interactions and protein anchoring modulate the modes of association of the globular domain of the Prion protein and Doppel protein to model membrane patches DOI Creative Commons
Patricia Soto,

Davis T. Thalhuber,

Frank Luceri

и другие.

Frontiers in Bioinformatics, Год журнала: 2024, Номер 3

Опубликована: Янв. 5, 2024

The Prion protein is the molecular hallmark of incurable prion diseases affecting mammals, including humans. protein-only hypothesis states that misfolding, accumulation, and deposition play a critical role in toxicity. cellular (PrP C ) anchors to extracellular leaflet plasma membrane prefers cholesterol- sphingomyelin-rich domains. Conformational conversion into pathological isoform happens on cell surface. In vitro vivo experiments indicate aggregation, toxicity are sensitive lipid composition membranes vesicles. A picture underlying biophysical driving forces explain effect - interactions physiological conditions needed develop structural model conformational conversion. To this end, we use dynamics simulations mimic between globular domain PrP anchored patches. addition, also simulate Doppel such closest phylogenetic tree , localizes an milieu similar exhibits topology even if amino acid sequence only 25% identical. Our show specific protein-lipid constraints imposed by GPI anchoring together favor binding sites but not Doppel. Interestingly, found correspond loops, which aggregation disease transmission barrier (β2-α2 loop) initial spontaneous misfolding (α2-α3 loop). We re-arranges locally accommodate residues inserted surface as response binding.

Язык: Английский

Процитировано

0