The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases

Schmitz, Matthias; Cramm, Maria; Llorens, Franc; Müller-Cramm, Dominik; Collins, Steven J.; Atarashi, Ryuichiro; Satoh, Katsuya; Orrú, Christina D.; Groveman, Bradley R.; Zafar, Saima; Schulz‐Schaeffer, Walter; Caughey, Byron; Zerr, Inga

doi:10.1038/nprot.2016.120

Cited by 109 publications

(84 citation statements)

References 54 publications

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“…RT‐QuIC analysis of CSF of patient 2 (obtained 10 days after the initial visit) was performed retrospectively (as described previously6) after obtaining the neuropathological result and was negative.…”

Section: Resultsmentioning

confidence: 99%

Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

Vicente-Pascual

Rossi

Gámez

et al. 2018

Ann Clin Transl Neurol

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We report clinico‐pathological features of a 65‐year‐old woman and a 56‐year‐old man with a 5‐year clinical history who had clinical and neuropathological characteristics of upper and lower motor neuron disease consistent with amyotrophic lateral sclerosis, and a frontotemporal atrophy pattern in case 2 without TDP‐43 pathology. Instead, spongiform change and pathological prion protein deposits were observed in several brain regions. No prion protein gene mutations were found. Western blot analysis showed a five‐band profile compatible with variably protease‐sensitive prionopathy. We conclude that this disease can display prolonged disease duration and clinico‐pathological features within the ALS/FTLD spectrum.

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Section: Resultsmentioning

confidence: 99%

Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

Vicente-Pascual

Rossi

Gámez

et al. 2018

Ann Clin Transl Neurol

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“…It is beyond the scope of this review to discuss this in detail. Three major technologies, reviewed elsewhere in great detail [10, 162, 192], are further discussed in the following.…”

Section: Alternatives To Animal Modelsmentioning

confidence: 99%

Prion disease: experimental models and reality

Brandner

Jaunmuktane

2017

Acta Neuropathol

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overview of the use of models of prion disease, how they have evolved alongside the scientific questions, and how advancements in technologies have pushed the boundaries of our understanding of prion biology. AbstractThe understanding of the pathogenesis and mechanisms of diseases requires a multidisciplinary approach, involving clinical observation, correlation to pathological processes, and modelling of disease mechanisms. It is an inherent challenge, and arguably impossible to generate model systems that can faithfully recapitulate all aspects of human disease. It is, therefore, important to be aware of the potentials and also the limitations of specific model systems. Model systems are usually designed to recapitulate only specific aspects of the disease, such as a pathological phenotype, a pathomechanism, or to test a hypothesis. Here, we evaluate and discuss model systems that were generated to understand clinical, pathological, genetic, biochemical, and epidemiological aspects of prion diseases. Whilst clinical research and studies on human tissue are an essential component of prion research, much of the understanding of the mechanisms governing transmission, replication, and toxicity comes from in vitro and in vivo studies. As with other neurodegenerative diseases caused by protein misfolding, the pathogenesis of prion disease is complex, full of conundra and contradictions. We will give here a historical Electronic supplementary material The online version of this article

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“…Analogous RT-QuIC assays for prion diseases (reviewed in [1, 5, 35, 40, 48]) can amplify prion seeding activity by a billion-to-trillion-fold, allowing detection of seeding activity in individuals’ cerebrospinal fluid (CSF) [1, 8, 26, 33], nasal brushings [32, 47], urine [28], and skin [36]. Such testing can provide intra vitam diagnoses that can be virtually 100% sensitive and specific [2, 34].…”

Section: Introductionmentioning

confidence: 99%

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease

Kraus¹,

Saijo²,

Metrick³

et al. 2018

Acta Neuropathol

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103

122

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Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD’s tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploited the seeded polymerization growth mechanism of tau filaments to develop a highly selective and ultrasensitive cell-free tau seed amplification assay optimized for AD (AD real-time quaking-induced conversion or AD RT-QuIC). The reaction is based on the ability of AD tau aggregates to seed the formation of amyloid fibrils made of certain recombinant tau fragments. AD RT-QuIC detected seeding activity in AD (n = 16) brains at dilutions as extreme as 107–1010-fold, but was 102–106-fold less responsive when seeded with brain from most cases of other types of tauopathy with comparable loads of predominant 3R or 4R tau aggregates. For example, AD brains had average seeding activities that were orders of magnitude higher than Pick disease brains with predominant 3R tau deposits, but the opposite was true using our previously described Pick-optimized tau RT-QuIC assay. CTE brains (n = 2) had seed concentrations comparable to the weakest of the AD specimens, and higher than 3 of 4 specimens with 3R/4R primary age-related tauopathy. AD seeds shared properties with the tau filaments found in AD brains, as AD seeds were sarkosyl-insoluble, protease resistant, and reactive with tau antibodies. Moreover, AD RT-QuIC detected as little as 16 fg of pure synthetic tau fibrils. The distinctive seeding activity exhibited by AD and CTE tau filaments compared to other types of tauopathies in these seeded polymerization reactions provides a mechanistic basis for their consistent propagation as specific conformers in patients with 3R/4R tau diseases. Importantly, AD RT-QuIC also provides rapid ultrasensitive quantitation of 3R/4R tau-seeding activity as a biomarker.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1947-3) contains supplementary material, which is available to authorized users.

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The real-time quaking-induced conversion assay for detection of human prion disease and study of other protein misfolding diseases

Cited by 109 publications

References 54 publications

Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

Variably protease‐sensitive prionopathy presenting within ALS/FTD spectrum

Prion disease: experimental models and reality

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease

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