PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

Bistaffa, Edoardo; Marín-Moreno, Alba; Espinosa, Juan Carlos; Luca, Chiara Maria Giulia De; Cazzaniga, Federico Angelo; Portaleone, Sara Maria; Celauro, Luigi; Legname, Giuseppe; Giaccone, Giorgio; Torres, Juan María; Moda, Fabio

doi:10.7554/elife.65311

Cited by 4 publications

(4 citation statements)

References 45 publications

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“…Regarding the potential for the human NC to shed infectious prions, studies using transgenic mice have shown that OM pellets collected from sporadic CJD is infectious, but the amount of infectivity in the OM brushings was more than 10,000-fold less infectious per unit volume than that for infected brain tissue from these same patients. These findings were similar to the results of a transmission study demonstrating that PMCA-generated products from OM obtained from FFI patients inoculated into transgenic mice expressing the bank vole prion protein were infectious [89]. To date, there has been just one study of human nasal secretions (collected from the nasal vestibule), which found prion infectivity in two of 13 samples, indicating that there was lower, and in most cases undetectable, seeding activity in the nasal secretions compared to the OM nasal brushings [90].…”

Section: Evidence From Human Prion Diseasessupporting

confidence: 88%

“…To date, there has been just one study of human nasal secretions (collected from the nasal vestibule), which found prion infectivity in two of 13 samples, indicating that there was lower, and in most cases undetectable, seeding activity in the nasal secretions compared to the OM nasal brushings [90]. Therefore, while the data suggest that the potential for the spread of prion diseases between humans is limited, precautions during surgical procedures involving the nasal cavity are warranted [89,90].…”

Section: Evidence From Human Prion Diseasesmentioning

confidence: 99%

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The Role of the Nasal Cavity in the Pathogenesis of Prion Diseases

Kincaid

2021

Viruses

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Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a class of fatal neurodegenerative diseases caused by the entry and spread of infectious prion proteins (PrPSc) in the central nervous system (CNS). These diseases are endemic to certain mammalian animal species that use their sense of smell for a variety of purposes and therefore expose their nasal cavity (NC) to PrPSc in the environment. Prion diseases that affect humans are either inherited due to a mutation of the gene that encodes the prion protein, acquired by exposure to contaminated tissues or medical devices, or develop without a known cause (referred to as sporadic). The purpose of this review is to identify components of the NC that are involved in prion transport and to summarize the evidence that the NC serves as a route of entry (centripetal spread) and/or a source of shedding (centrifugal spread) of PrPSc, and thus plays a role in the pathogenesis of the TSEs.

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Section: Evidence From Human Prion Diseasessupporting

confidence: 88%

Section: Evidence From Human Prion Diseasesmentioning

confidence: 99%

The Role of the Nasal Cavity in the Pathogenesis of Prion Diseases

Kincaid

2021

Viruses

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“…Generally, PMCA products possess both biochemical characteristics and infectivity of prions, whereas RT-QuIC products are more of a ref lection of prion fibrillation [19][20][21], which usually lack infectivity [22]. Overcoming natural species barriers of prion infection is observed in the experimental bioassays of PMCA product inoculation.…”

Section: Hamster-and Mouse-adapted Scrapie Agents Failed To Induce Co...mentioning

confidence: 99%

PRNP Sequences of Tibetan Antelope, Blue Sheep, and Plateau Pika from the Qinghai-Tibet Plateau and Reactivity of PrP Proteins to Rodent-Adapted Scrapie Strains in RT-QuIC and PMCA

Yang

et al. 2023

Zoonoses

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Background: Tibetan antelope (Rhinopithecus), blue sheep (Pseudois nayauris), and plateau pika (Ochotona curzoniae) are wild animals living on the Qinghai-Tibet Plateau. There have been no reports of naturally-occurring transmissible spongioform encephalopathies (TSEs) involving these animals. Furthermore, the PRNP genes have not been described in the literature. Methods: The PRNP genes from 21 Tibetan antelopes, 4 blue sheep, and 3 plateau pikas were obtained and sequenced. The recombinant proteins were then prepared. Using scrapie strains (263K, 139A, ME7, and S15) as the seeds, the reactivity of the PrP proteins from sheep (rSheepPrP25-234) and pika (rPikaPrP23-230) were tested using real-time quaking-induced conversion (RT-QuIC). Protein misfolding cyclic amplification (PMCA) tests of the brain homogenates from domestic sheep and rabbits were performed with the seeds of strains 263K and ME7. Results: The PRNP genes of bovids were 771 bp long and encoded 256 amino acids (aa), showing 100% homology with the wild-type sheep prion protein (PrP) aa sequence. The PRNP gene of pika was 759 bp long and encoded 252 amino acids, showing 92.1% homology with the aa sequence of domestic rabbits. The sheep and pika proteins revealed positive reactions in 10-5 diluted seeds. Only rPikaPrP23-230 produced positive curves in 10-7 diluted seeds. The PMCA tests failed to produce proteinase K (PK)-resistant PrP (PrPres). Conclusion: This is the first description of PRNP genes and PrP aa sequences of Tibetan antelope, blue sheep, and plateau pike from the Qinghai-Tibet Plateau. In the presence of rodent prions, the PrPs of sheep and pika efficiently induce fibrillation in RT-QuIC, but do not generate PrPres in PMCA. Our results indicate that pika, as one of the important links in the Qinghai-Tibet Plateau biological chain, may play an important role in the prion circulation. Pika PrP deserves further analysis for its potential application value in assays for human prion disease.

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“…The transmissible nature of prions means that they can self-propagate or seed the conversion of normal PrP into prions. This seeding ability allows the disease to spread through the brain and can be measured by highly sensitive and specific assays such as Real-time Quaking-Induced Conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) [7][8][9]. The D178N mutation does not result in steady-state production of prions in cell culture models; however, it directly alters the biochemical properties of PrP, producing heavily glycosylated PrP [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction

et al. 2023

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Fatal familial insomnia (FFI) is a rare neurodegenerative disease caused by a dominantly inherited single amino acid substitution (D178N) within the prion protein (PrP). No in vitro human brain tissue model for this disease has previously been available. Consequently, how this mutation exerts its damaging effect on brain cells is still unknown. Using CRISPR-Cas9 engineered induced pluripotent stem cells, we made D178N cerebral organoids and compared these with isotype control organoids. We found that, in the absence of other hallmarks of FFI, the D178N organoids exhibited astrogliosis with cellular oxidative stress. Abnormal post-translational processing of PrP was evident but no tissue deposition or propagation of mis-folded PrP isoforms were observed. Neuronal electrophysiological function was compromised and levels of neurotransmitters, particularly acetylcholine and GABA, altered. Underlying these dysfunctions were changes in cellular energy homeostasis, with substantially increased glycolytic and Krebs cycle intermediates, and greater mitochondrial activity. This increased energy demand in D178N organoids was associated with increased mitophagy and depletion of lipid droplets, in turn resulting in shifts of cellular lipid composition. Using a double mutation (178NN) we could confirm that most changes were caused by the presence of the mutation rather than interaction with PrP molecules lacking the mutation. Our data strongly suggests that shifting biosynthetic intermediates and oxidative stress, caused by an imbalance of energy supply and demand, results in astrogliosis with compromised neuronal activity in FFI organoids. They further support that many of the disease associated changes are due to a corruption of PrP function and do not require propagation of PrP mis-folding.

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PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice

Cited by 4 publications

References 45 publications

The Role of the Nasal Cavity in the Pathogenesis of Prion Diseases

The Role of the Nasal Cavity in the Pathogenesis of Prion Diseases

PRNP Sequences of Tibetan Antelope, Blue Sheep, and Plateau Pika from the Qinghai-Tibet Plateau and Reactivity of PrP Proteins to Rodent-Adapted Scrapie Strains in RT-QuIC and PMCA

Altered energy metabolism in Fatal Familial Insomnia cerebral organoids is associated with astrogliosis and neuronal dysfunction

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