Enhanced quantitation of pathological α-synuclein in patient biospecimens by RT-QuIC seed amplification assays.

Disease associated pathological aggregates of alpha-synuclein (αSynD) exhibit prion-like spreading in synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Seed amplification assays (SAAs) such as real-time quaking-induced conversion (RT-QuIC) have shown high diagnostic sensitivity and specificity for detecting proteopathic αSynD seeds in a variety of biospecimens from PD and DLB patients. However, the extent to which relative proteopathic seed concentrations are useful as indices of a patient's disease stage or prognosis remains unresolved.

Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson's disease.

Background: Seed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson's disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation.

Skin α-Synuclein Seeding Activity in Patients with Type 1 Gaucher Disease.

Background: Patients with type 1 Gaucher disease (GD1) have a significantly increased risk of developing Parkinson's disease (PD).

Objective: The objective of this study was to evaluate skin α-synuclein (αSyn) seeding activity as a biomarker for GD1-related PD (GD1-PD).

Methods: This single-center study administered motor and cognitive examinations and questionnaires of nonmotor symptoms to adult patients with GD1.

Genetic insights into drug targets for sporadic Creutzfeldt-Jakob disease: Integrative multi-omics analysis.

Objective: Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data.

Methods: Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues.

First Report of Single Nucleotide Polymorphisms (SNPs) of the Leporine Shadow of Prion Protein Gene () and Absence of Nonsynonymous SNPs in the Open Reading Frame (ORF) in Rabbits.

Prion disorders are fatal infectious diseases that are caused by a buildup of pathogenic prion protein (PrP) in susceptible mammals. According to new findings, the shadow of prion protein (Sho) encoded by the shadow of prion protein gene () is associated with prion protein (PrP), promoting the progression of prion diseases. Although genetic polymorphisms in are associated with susceptibility to several prion diseases, genetic polymorphisms in the rabbit gene have not been investigated in depth.

Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease.

Objectives: To elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities.

Methods: The genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included.

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

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.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrP). Our previous study revealed that PrP-seeding activity (PrP-SA) is detectable in skin of sCJD patients by an ultrasensitive PrP seed amplification assay (PrP-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls.

The first report of polymorphisms of the prion protein gene () in Pekin ducks ().

Background: Prion diseases have been extensively reported in various mammalian species and are caused by a pathogenic prion protein (PrP), which is a misfolded version of cellular prion protein (PrP). Notably, no cases of prion disease have been reported in birds. Single nucleotide polymorphisms (SNPs) of the prion protein gene () that encodes PrP have been associated with susceptibility to prion diseases in several species.

Y225A induces long-range conformational changes in human prion protein that are protective in Drosophila.

Prion protein (PrP) misfolding is the key trigger in the devastating prion diseases. Yet the sequence and structural determinants of PrP conformation and toxicity are not known in detail. Here, we describe the impact of replacing Y225 in human PrP with A225 from rabbit PrP, an animal highly resistant to prion diseases.

Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function.

Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is directly linked to PrP dysfunction. We differentiated cardiomyocyte cultures from donor human induced pluripotent stem cells and found a direct influence of the PRNP E200K mutation on cellular function.

Selective Detection of Misfolded Tau From Postmortem Alzheimer's Disease Brains.

Tau aggregates are present in multiple neurodegenerative diseases known as "tauopathies," including Alzheimer's disease, Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Such misfolded tau aggregates are therefore potential sources for selective detection and biomarker discovery. Six human tau isoforms present in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions.

Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study.

Skin α-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of α-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of α-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study.

Generation of human chronic wasting disease in transgenic mice.

Chronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrP) of cellular prion protein (PrP). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.

Modulation of Neuroinflammation by the Gut Microbiota in Prion and Prion-Like Diseases.

The process of neuroinflammation contributes to the pathogenic mechanism of many neurodegenerative diseases. The deleterious attributes of neuroinflammation involve aberrant and uncontrolled activation of glia, which can result in damage to proximal brain parenchyma. Failure to distinguish self from non-self, as well as leukocyte reaction to aggregation and accumulation of proteins in the CNS, are the primary mechanisms by which neuroinflammation is initiated.

Further Characterization of Glycoform-Selective Prions of Variably Protease-Sensitive Prionopathy.

Prion is an infectious protein (PrP) that is derived from a cellular glycoprotein (PrP) through a conformational transition and associated with a group of prion diseases in animals and humans. Characterization of proteinase K (PK)-resistant PrP by western blotting has been critical to diagnosis and understanding of prion diseases including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) disease in humans. However, formation as well as biochemical and biological properties of the glycoform-selective PrP in variably protease-sensitive prionopathy (VPSPr) remain poorly understood.

Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson's disease and dementia with Lewy bodies.

Definitive diagnosis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSyn) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSyn aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSyn across a wide range of biospecimens and in different laboratories.

Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease.

Importance: Deposition of the pathological α-synuclein (αSynP) in the brain is the hallmark of synucleinopathies, including Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). Whether real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays can sensitively detect skin biomarkers for PD and non-PD synucleinopathies remains unknown.

Objective: To develop sensitive and specific skin biomarkers for antemortem diagnosis of PD and other synucleinopathies.

Assessment of the Sensitivity and Specificity of the Established Real-time Quaking-induced Conversion (RT-QuIC) Technique in Chinese CJD Surveillance.

Real-time quaking-induced conversion (RT-QuIC) assay is a newly established PrP -detecting method. The development of RT-QuIC improves the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), showing good sensitivity and specificity in many countries when the method was used in cerebrospinal fluid (CSF) samples. However, in China, the sensitivity and specificity of RT-QuIC has yet to be determined due to the lack of definitive diagnosis samples.

Characterization of Anchorless Human PrP With Q227X Stop Mutation Linked to Gerstmann-Sträussler-Scheinker Syndrome In Vivo and In Vitro.

Alteration in cellular prion protein (PrP) localization on the cell surface through mediation of the glycosylphosphatidylinositol (GPI) anchor has been reported to dramatically affect the formation and infectivity of its pathological isoform (PrP). A patient with Gerstmann-Sträussler-Scheinker (GSS) syndrome was previously found to have a nonsense heterozygous PrP-Q227X mutation resulting in an anchorless PrP. However, the allelic origin of this anchorless PrP and cellular trafficking of PrP remain to be determined.

Publisher Correction: Early preclinical detection of prions in the skin of prion-infected animals.

The original version of this Article contained errors in the author affiliations. Affiliation 2 incorrectly read 'Department of Neurology, The First Hospital of Jilin University, Changchun 130021 Jilin Province, China.'Affiliation 5 incorrectly read 'Department of Otolaryngology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061 Shanxi Province, China'Affiliation 9 incorrectly read 'State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.