Convergent generation of atypical prions in knockin mouse models of genetic prion disease

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(15)

Опубликована: Июль 31, 2024

Most cases of human prion disease arise due to spontaneous misfolding WT or mutant protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether generation can occur within the mouse lifespan absence protein overexpression and how disease-causing mutations affect strain properties. To address these issues, we generated knockin mice that express misfolding-prone bank vole (BVPrP). While expressing BVPrP (I109 variant) remained free from neurological disease, a subset with (D178N E200K) causing genetic developed progressive illness. Brains spontaneously ill contained disease-specific neuropathological changes as well atypical protease-resistant BVPrP. Moreover, brain extracts D178N- E200K-mutant BVPrP-knockin exhibited seeding activity transmitted Surprisingly, properties prions appeared identical before after transmission, suggesting both guide formation similar strain. These findings imply develop bona fide diseases may share uniform initial mechanism action.

Язык: Английский

---

Modulating α-synuclein propagation and decomposition: Implications in Parkinson's disease therapy

Ageing Research Reviews, Год журнала: 2024, Номер 98, С. 102319 - 102319

Опубликована: Май 6, 2024

Язык: Английский

---

Small molecule modulators of Alpha-Synuclein Aggregation and Toxicity: Pioneering an Emerging Arsenal Against Parkinson’s Disease

Ageing Research Reviews, Год журнала: 2024, Номер 101, С. 102538 - 102538

Опубликована: Окт. 9, 2024

Язык: Английский

---

Anti-prion drugs do not improve survival in novel knock-in models of inherited prion disease

PLoS Pathogens, Год журнала: 2024, Номер 20(4), С. e1012087 - e1012087

Опубликована: Апрель 1, 2024

Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic infectious versions, while mutant cause inherited variants like fatal familial insomnia (FFI) Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold rodent models of diseases, no effective treatments FFI fCJD have been found. In this study, we evaluated efficacy various anti-prion on newly-developed knock-in mouse fCJD. These express bank vole protein (PrP) with pathogenic D178N E200K mutations. We applied drug regimens known be highly against wild-type vivo as well a brain-penetrant compound that inhibits PrP Sc propagation vitro . None tested (Anle138b, IND24, Anle138b + cellulose ether, PSCMA) significantly extended disease-free survival or prevented accumulation either model, despite their ability induce strain adaptation prions. Our results show originally developed treat do not necessarily work recombinant sPMCA is reliable platform identifying compounds target This underscores need develop therapies validate screening assays specifically prions, strategies strain-dependent.

Язык: Английский

---

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Pharmaceutics, Год журнала: 2023, Номер 15(8), С. 2051 - 2051

Опубликована: Июль 30, 2023

α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, regulates vesicle trafficking and neurotransmitter release presynaptic terminals. Pathologies related to misfolding aggregation of α-syn are referred as α-synucleinopathies, they constitute a frequent cause neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), caused by abnormal accumulation dopaminergic neurons midbrain. This results overload, activation endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis To date, available treatment options for PD only symptomatic rely on dopamine replacement therapy or palliative surgery. As prevalence has skyrocketed recent years, there pending issue development new disease-modifying strategies. These include anti-aggregative agents that target directly (gene therapy, small molecules immunization), indirectly (modulators ER oxidative stress clearance pathways) combine both actions (natural compounds). Herein, we provide overview characteristic features structure pathogenic mechanisms could be targeted with novel molecular-based therapies.

Язык: Английский

---

Human prion diseases - state of the art 2023

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.

---

Combination of Styrylbenzoazole Compound and Hydroxypropyl Methylcellulose Enhances Therapeutic Effect in Prion-Infected Mice

Molecular Neurobiology, Год журнала: 2023, Номер 61(7), С. 4705 - 4711

Опубликована: Дек. 20, 2023

Abstract Prion diseases are fatal transmissible neurodegenerative disorders. Tremendous efforts have been made for prion diseases; however, no effective treatment is available. Several anti-prion compounds a preference which strains or prion-infected animal models to target. Styrylbenzoazole compound called cpd-B in RML mice but less so 263K mice, whereas hydroxypropyl methylcellulose mice. In the present study, we developed combination therapy of and expecting synergistic effects both A single subcutaneous administration this had substantially effect additive These results showed that was enhanced by methylcellulose. The complementary nature two efficacy against strains, chemical properties, pharmacokinetics, physical properties appears contributed therapy. Our pave way strategy new agents.

Язык: Английский

---

Improvement of anti-prion efficacy with stearoxy conjugation of hydroxypropyl methylcellulose in prion-infected mice

Carbohydrate Polymers, Год журнала: 2024, Номер 337, С. 122163 - 122163

Опубликована: Апрель 16, 2024

Prion diseases are fatal transmissible neurodegenerative disorders. Among known anti-prions, hydroxypropyl methylcellulose compounds (HPMCs) unique in their chemical structure and action. They have several excellent anti-prion properties but the effectiveness depends on prion-infected mouse model. In present study, we investigated effects of stearoxy-modified HPMCs cells mice. Stearoxy modification improved efficacy significantly prolonged incubation period a lower HPMC-responding However, stearoxy showed no improvement over nonmodified an These results offer new line inquiry for use with mice that do not respond well to HPMCs.

Язык: Английский

---

The prion protein is required for normal responses to light stimuli by photoreceptors and bipolar cells

iScience, Год журнала: 2024, Номер 27(10), С. 110954 - 110954

Опубликована: Сен. 13, 2024

Язык: Английский

---

Hypothesis: functional age and onset of autosomal dominant genetic prion disease

Theory in Biosciences, Год журнала: 2023, Номер 142(2), С. 143 - 150

Опубликована: Апрель 5, 2023

Язык: Английский

---