Real-Time Quaking-Induced Conversion (QuIC) Assays for the Detection and Diagnosis of Human Prion Diseases

Orrú, Christina D.; Isiofia, Onyekachi; Hughson, Andrew G.; Caughey, Byron

doi:10.1007/978-3-031-20565-1_30

Cited by 5 publications

(5 citation statements)

References 86 publications

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“…The seed-ampli cation assay (SAA) technology, utilizing real-time quaking-induced conversion (RT-QuIC) or protein misfolding cyclic ampli cation (PMCA), offers an ultrasensitive approach to identify disease-speci c biomarkers in easily accessible specimens for early diagnosis and disease progression assessment [6][7][8]. This technology has been used to detect prions and other prion-like misfolded proteins such as α-synuclein in body uids and peripheral tissues of PrD and PD by assessing the seeding activity (SA) of misfolded proteins [9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies

Wang,

Wu,

Gerasimenko

et al. 2024

Preprint

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Background Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically phosphorylated tau protein in the brain, leading to prion-like propagation and aggregation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking. Methods We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls. Results We found that the skin prion-SAA demonstrated a significantly higher sensitivity (75–80%) and specificity (95–100%) for detecting tauopathy, depending on the tau substrates used. Moreover, increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used. Conclusions Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.

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Section: Introductionmentioning

confidence: 99%

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies

Wang,

Wu,

Gerasimenko

et al. 2024

Preprint

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“…The ultrasensitive technology termed seed-amplification assay (SAA) of misfolded proteins by either real time quaking-induced conversion (RT-QuIC) or protein misfolding cyclic amplification assay (PMCA) has made it possible to identify new biomarkers in easily accessible specimens for early diagnosis and assessment of disease progression [36, 41, 57]. It has been widely used in the detection not only of prions but also other prion-like misfolded proteins such as αSyn and tau in body fluids and peripheral tissues of PrD and PD by detecting the seeding activity (SA) of misfolded proteins [4, 14, 18, 39, 40, 47, 50].…”

Section: Introductionmentioning

confidence: 99%

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

Wang,

Wu,

Gerasimenko

et al. 2023

Preprint

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Tauopathies are a group of age-related neurodegenerative diseases with a molecular hallmark of the prion-like propagation and accumulation of pathologically phosphorylated tau protein in the brain. They include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Currently, in the peripheral tissues and body fluids there are no reliable diagnostic biomarkers available that are able to directly reflect the capability of propagation and spreading of the misfolded tau aggregates. Here, we revealed significantly increased amounts of phosphorylated tau in the skin of AD patients compared to those in other tauopathies and normal controls. Moreover, the seed-amplification assay (SAA) by the ultrasensitive real-time quaking-induced conversion (RT-QuIC) displayed that the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies including AD, PSP, CBD, PiD was dramatically higher than that in normal controls, yielding 75-80% sensitivity and 95-100% specificity, respectively, depending on different tau substrates used. The increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients. Moreover, analysis of the end products of skin-tau SAA confirmed that the increased seeding activity is accompanied with formation of tau aggregates that are of different physicochemical properties determined by the different tau-substrates used. Our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of the skin misfolded tau can serve as an accurate diagnostic biomarker of tauopathies.

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“…The detection of both human (PD) and animal (CWD) proteinopathies was recently enhanced by various assays involving the amplification of protein misfolding in vitro, including protein misfolding cyclic amplification (PMCA) 18,23,[37][38][39] , end-point quaking-induced conversion (EP-QuIC) 40,41 and real-time quaking-induced conversion (RT-QuIC) 4,23,[42][43][44][45][46][47][48][49] . These assays are also known as seeded amplification assays (SAAs).…”

mentioning

confidence: 99%

Visual detection of misfolded alpha-synuclein and prions via capillary-based quaking-induced conversion assay (Cap-QuIC)

Christenson,

Jeong,

Ahn

et al. 2024

npj Biosensing

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Neurodegenerative protein misfolding diseases impact tens of millions of people worldwide, contributing to millions of deaths and economic hardships across multiple scales. The prevalence of neurodegenerative disease is predicted to greatly increase over the coming decades, yet effective diagnostics for such diseases are limited. Most diagnoses come from the observation of external symptoms in clinical settings, which typically manifest during relatively advanced stages of disease, thus limiting potential therapeutic applications. While progress is being made on biomarker testing, the underlying methods largely rely on fragile and expensive equipment that limits their point-of-care potential, especially in developing countries. Here we present Capillary-based Quaking Induced Conversion (Cap-QuIC) as a visual diagnostic assay based on simple capillary action for the detection of neurodegenerative disease without necessitating expensive and complex capital equipment. We demonstrate that Cap-QuIC has the potential to be a detection tool for a broad range of misfolded proteins by successfully distinguishing misfolded versus healthy proteins associated with Parkinson’s disease (α-synuclein) and Chronic Wasting Disease (prions). Additionally, we show that Cap-QuIC can accurately classify biological tissue samples from wild white-tailed deer infected with Chronic Wasting Disease. Our findings elucidate the underlying mechanism that enables the Cap-QuIC assay to distinguish misfolded protein, highlighting its potential as a diagnostic technology for neurodegenerative diseases.

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Real-Time Quaking-Induced Conversion (QuIC) Assays for the Detection and Diagnosis of Human Prion Diseases

Cited by 5 publications

References 86 publications

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies

Seeding Activity of Skin Misfolded Tau as a Biomarker for Tauopathies

Seeding Activity of Skin Misfolded Tau as a Novel Biomarker for Tauopathies

Visual detection of misfolded alpha-synuclein and prions via capillary-based quaking-induced conversion assay (Cap-QuIC)

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