Detection of prion seeding activity in the olfactory mucosa of patients with Fatal Familial Insomnia

Redaelli, Veronica; Bistaffa, Edoardo; Zanusso, Gianluigi; Salzano, Giulia; Sacchetto, Luca; Rossi, Martina; Luca, Chiara Maria Giulia De; Bari, Michele Di; Portaleone, Sara Maria; Agrimi, Umberto; Legname, Giuseppe; Roiter, Ignazio; Forloni, Gianluigi; Tagliavini, Fabrizio; Moda, Fabio

doi:10.1038/srep46269

Cited by 41 publications

(33 citation statements)

References 35 publications

(51 reference statements)

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“…At present, no solid results indicate that PMCA can efficiently amplify other human prions, especially those associated with sCJD [66]. Certainly, these limitations depend on the experimental conditions used and increasing evidence suggests that their modifications could lead to a successful amplification of sCJD strains [66][67][68][69].…”

Section: Protein Misfolding Cyclic Amplification (Pmca)mentioning

confidence: 99%

“…In 2017, Redaelli V. and coworkers adapted the PMCA technology for the detection of PrP Sc in the olfactory mucosa (OM) of two patients with FFI [68]. Samples were collected in the late stage of the disease.…”

Section: Pmca Detected Prions In the Olfactory Mucosa Of Patients Witmentioning

confidence: 99%

“…Our group is currently working on PMCA optimization for the analysis of OM samples collected from sCJD patients and has gathered promising results that are currently under evaluation before any significant conclusion might be drawn. Besides the work of Redaelli et al [68], no other studies on the capability of PMCA to detect prions in OM of patients with other genetic forms of prion diseases were reported. Similarly, crucial information about the infectivity of OM when challenged in mice is still lacking.…”

Section: Pmca Detected Prions In the Olfactory Mucosa Of Patients Witmentioning

confidence: 99%

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PMCA Applications for Prion Detection in Peripheral Tissues of Patients with Variant Creutzfeldt-Jakob Disease

Giaccone

Moda

2020

Biomolecules

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Prion diseases are neurodegenerative and invariably fatal conditions that affect humans and animals. In particular, Creutzfeldt-Jakob disease (CJD) and bovine spongiform encephalopathy (BSE) are paradigmatic forms of human and animal prion diseases, respectively. Human exposure to BSE through contaminated food caused the appearance of the new variant form of CJD (vCJD). These diseases are caused by an abnormal prion protein named PrPSc (or prion), which accumulates in the brain and leads to the onset of the disease. Their definite diagnosis can be formulated only at post-mortem after biochemical and neuropathological identification of PrPSc. Thanks to the advent of an innovative technique named protein misfolding cyclic amplification (PMCA), traces of PrPSc, undetectable with the standard diagnostic techniques, were found in peripheral tissues of patients with vCJD, even at preclinical stages. The technology is currently being used in specialized laboratories and can be exploited for helping physicians in formulating an early and definite diagnosis of vCJD using peripheral tissues. However, this assay is currently unable to detect prions associated with the sporadic CJD (sCJD) forms, which are more frequent than vCJD. This review will focus on the most recent advances and applications of PMCA in the field of vCJD and other human prion disease diagnosis.

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Section: Protein Misfolding Cyclic Amplification (Pmca)mentioning

confidence: 99%

Section: Pmca Detected Prions In the Olfactory Mucosa Of Patients Witmentioning

confidence: 99%

Section: Pmca Detected Prions In the Olfactory Mucosa Of Patients Witmentioning

confidence: 99%

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PMCA Applications for Prion Detection in Peripheral Tissues of Patients with Variant Creutzfeldt-Jakob Disease

Giaccone

Moda

2020

Biomolecules

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“…Both PMCA and RT-QuIC on nasal brushings of two FFI patients demonstrated that in this genetic prion disease, PrP Sc can also be found in trace amounts in olfactory mucosa samples. Both techniques were able to detect as little as femtogram amounts of PrP Sc in nasal brushings of FFI-affected patients, with 100% specificity and quantitative PMCA allowed to estimate PrP Sc concentration on these samples of 1.41 × 10 −14 g/mL [275]. Another control-case study in olfactory mucosa was performed with samples from 86 CJD patients (probable, possible and suspected cases) versus 104 controls analyzed by RT-QuIC.…”

Section: Cell-free Prion Propagation Systems and Prp Sc Detection In mentioning

confidence: 99%

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

et al. 2020

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Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and was only possible by histopathological and immunohistochemical analysis of the brain at necropsy. Although surrogate biomarkers of neurological damage have become invaluable to complement clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases show similar alterations hindering the differential diagnosis. To solve that, the detection of the pathognomonic biomarker of disease, PrP Sc , the aberrantly folded isoform of the prion protein, could be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early clinical stages are extremely low for the standard detection methods. The solution comes from the recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been already applied to detect minute amounts of PrP Sc in different matrixes and make early diagnosis of prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which PrP Sc has been detected in animals and humans are being reviewed, especially those in which cell-free prion propagation systems have been used with diagnostic purposes.

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“…Despite this highly specific biomarker is known since several decades, only very recently has been possible to exploit it for early diagnosis. Indeed, the advancements of in vitro amplification techniques such as PMCA and RT‐QuIC make now possible to identify different prion diseases by analyzing blood (Bougard et al, ; Concha‐Marambio et al, ), urine (Moda et al, ), CSF (McGuire et al, ), and nasal brushings (Orru et al, ; Redaelli et al, ) samples. The use of these techniques, which allow early diagnosis, could also provide a new time window for timely therapeutic intervention.…”

Section: Prpc and Prpsc: Ying And Yang Of The Prion Proteinmentioning

confidence: 99%

Brain aging: A Ianus‐faced player between health and neurodegeneration

Vanni

Baldeschi

Zattoni

et al. 2019

J of Neuroscience Research

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Neurodegenerative diseases are incurable debilitating disorders characterized by structural and functional neuronal loss. Approximately 30 million people are affected worldwide, and this number is predicted to reach more than 150 million by 2050. Neurodegenerative disorders include Alzheimer’s, Parkinson’s, and prion diseases among others. These disorders are characterized by the accumulation of aggregating proteins forming amyloid, responsible for the disease‐associated pathological lesions. The aggregation of amyloidogenic proteins can result either in gaining of toxic functions, derived from the damage provoked by these deposits in affected tissue, or in a loss of functions, due to the sequestration and the consequent inability of the aggregating protein to ensure its physiological role. While it is widely accepted that aging represents the main risk factor for neurodegeneration, there is still no clear cut‐off line between the two conditions. Indeed, many of the pathways that are commonly altered in neurodegeneration—misfolded protein accumulation, chronic inflammation, mitochondrial dysfunction, impaired iron homeostasis, epigenetic modifications—have been often correlated also with healthy aging. This overlap could be explained by the fact that the continuous accumulation of cellular damages, together with a progressive decline in metabolic efficiency during aging, makes the neurons more vulnerable to toxic injuries. When a given threshold is exceeded, all these alterations might give rise to pathological phenotypes that ultimately lead to neurodegeneration.

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Detection of prion seeding activity in the olfactory mucosa of patients with Fatal Familial Insomnia

Cited by 41 publications

References 35 publications

PMCA Applications for Prion Detection in Peripheral Tissues of Patients with Variant Creutzfeldt-Jakob Disease

PMCA Applications for Prion Detection in Peripheral Tissues of Patients with Variant Creutzfeldt-Jakob Disease

Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases

Brain aging: A Ianus‐faced player between health and neurodegeneration

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