Dataset Information

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

ABSTRACT: Fatal Familial Insomnia (FFI) is a genetic prion disease caused by a point mutation in the prion protein gene (PRNP) characterized by prominent thalamic atrophy, diffuse astrogliosis and moderate deposition of PrP^Sc in the brain. Here, for the first time, we demonstrate that the olfactory mucosa (OM) of patients with FFI contains trace amount of PrP^Sc detectable by PMCA and RT-QuIC. Quantitative PMCA analysis estimated a PrP^Sc concentration of about 1?×?10^-14?g/ml. In contrast, PrP^Sc was not detected in OM samples from healthy controls and patients affected by other neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and frontotemporal dementia. These results indicate that the detection limit of these assays is in the order of a single PrP^Sc oligomer/molecule with a specificity of 100%.

SUBMITTER: Redaelli V

PROVIDER: S-EPMC5384244 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Redaelli Veronica V Bistaffa Edoardo E Zanusso Gianluigi G Salzano Giulia G Sacchetto Luca L Rossi Martina M De Luca Chiara Maria Giulia CM Di Bari Michele M Portaleone Sara Maria SM Agrimi Umberto U Legname Giuseppe G Roiter Ignazio I Forloni Gianluigi G Tagliavini Fabrizio F Moda Fabio F

Scientific reports 20170407

Fatal Familial Insomnia (FFI) is a genetic prion disease caused by a point mutation in the prion protein gene (PRNP) characterized by prominent thalamic atrophy, diffuse astrogliosis and moderate deposition of PrPSc in the brain. Here, for the first time, we demonstrate that the olfactory mucosa (OM) of patients with FFI contains trace amount of PrPSc detectable by PMCA and RT-QuIC. Quantitative PMCA analysis estimated a PrPSc concentration of about 1 × 10-1 ...[more]

PMID: 28387370

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Project description:BackgroundParkinson's disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal ?-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either ?-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of ?-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM).MethodsWe have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant ?-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce ?-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP.ResultsOur results showed that a significant percentage of MSA and PD samples induced ?-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination.ConclusionsOur study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for ?-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages.

Dataset Information

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

Publications

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

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