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Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
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Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide , Enfermedades Neurodegenerativas , Humanos , Proteína ADAM10/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Proteínas Priónicas/metabolismo , Proteínas de la Membrana/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , AnticuerposRESUMEN
BACKGROUND: Accurate diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) represents a health issue due to the absence of disease traits. We assessed the performance of a SIMOA panel in cerebrospinal fluid (CSF) from 43 AD and 33 FTD patients with 60 matching Control subjects in combination with demographic-clinical characteristics. METHODS: 136 subjects (AD: n = 43, FTD: n = 33, Controls: n = 60) participated. Single-molecule array (SIMOA), glial fibrillary acidic protein (GFAP), neurofilament light (NfL), TAU, and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in CSF were analyzed with a multiplex neuro 4plex kit. Receiver operating characteristic (ROC) curve analysis compared area under the curve (AUC), while the principal of the sparse partial least squares discriminant analysis (sPLS-DA) was used with the intent to strengthen the identification of confident disease clusters. RESULTS: CSF exhibited increased levels of all SIMOA biomarkers in AD compared to Controls (AUCs: 0.71, 0.86, 0.92, and 0.94, respectively). Similar patterns were observed in FTD with NfL, TAU, and UCH-L1 (AUCs: 0.85, 0.72, and 0.91). sPLS-DA revealed two components explaining 19% and 9% of dataset variation. CONCLUSIONS: CSF data provide high diagnostic accuracy among AD, FTD, and Control discrimination. Subgroups of demographic-clinical characteristics and biomarker concentration highlighted the potential of combining different kinds of data for successful and more efficient cohort clustering.
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Organic photocatalysts frequently possess dual singlet and triplet photoreactivity and a thorough photochemical characterization is essential for efficient light-driven applications. In this article, the mode of action of a polyazahelicene catalyst (Aza-H) was investigated using laser flash photolysis (LFP). The study revealed that the chromophore can function as a singlet-state photoredox catalyst in the sulfonylation/arylation of styrenes and as a triplet sensitizer in energy transfer catalysis. The singlet lifetime is sufficiently long to exploit the exceptional excited state reduction potential for the activation of 4-cyanopyridine. Photoinduced electron transfer generating the radical cation was directly observed confirming the previously proposed mechanism of a three-component reaction. Several steps of the photoredox cycle were investigated separately, providing deep insights into the complex mechanism. The triplet-excited Aza-H, which was studied with quantitative LFP, is formed with a quantum yield of 0.34. The pronounced triplet formation was exploited for the isomerization reaction of (E)-stilbene to the Z-isomer and the cyclization of cinnamyl chloride. Catalyst degradation mainly occurs through the long-lived Aza-H triplet (28 µs), but the photostability is greatly increased when the triplet efficiently reacts in a catalytic cycle such that turnover numbers exceeding 4400 are achievable with this organocatalyst.
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Prions are proteinaceous pathogens responsible for a variety of devastating diseases in mammals, including scrapie in sheep and goats, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by their exceptional persistence to common inactivation procedures. This applies to all possible sources of prion contamination as prions may be present in the tissues and biological fluids of infected individuals. Hence, efficient prion inactivation procedures are still being sought to minimize the risk of intra- or inter-species transmission. In the past, photocatalytic treatment has been proven to be capable of efficiently oxidizing and inactivating prions. In the present study, the efficacy of homogeneous photo-Fenton-based photocatalysis as well as heterogeneous photocatalysis with TiO2 in reducing RML mouse scrapie infectivity was evaluated. Prion inactivation was assessed by means of a bioassay, and the results were confirmed by in vitro experiments. While the prion infectivity of the RML mouse scrapie was reduced after treatment with the photo-Fenton reagent, the heterogeneous photocatalytic treatment of the same prion strain completely eliminated prion infectivity.
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Prion diseases, also known as Transmissible Spongiform Encephalopathies (TSEs), are protein-based neurodegenerative disorders (NDs) affecting humans and animals. They are characterized by the conformational conversion of the normal cellular prion protein, PrPC, into the pathogenic isoform, PrPSc. Prion diseases are invariably fatal and despite ongoing research, no effective prophylactic or therapeutic avenues are currently available. Anthocyanins (ACNs) are unique flavonoid compounds and interest in their use as potential neuroprotective and/or therapeutic agents against NDs, has increased significantly in recent years. Therefore, we investigated the potential anti-oxidant and anti-prion effects of Oenin and Myrtillin, two of the most common anthocyanins, using the most accepted in the field overexpressing PrPScin vitro model and a cell free protein aggregation model. Our results, indicate both anthocyanins as strong anti-oxidant compounds, upregulating the expression of genes involved in the anti-oxidant response, and reducing the levels of Reactive Oxygen Species (ROS), produced due to pathogenic prion infection, through the activation of the Keap1-Nrf2 pathway. Importantly, they showcased remarkable anti-prion potential, as they not only caused the clearance of pathogenic PrPSc aggregates, but also completely inhibited the formation of PrPSc fibrils in the Cerebrospinal Fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD). Therefore, Oenin and Myrtillin possess pleiotropic effects, suggesting their potential use as promising preventive and/or therapeutic agents in prion diseases and possibly in the spectrum of neurodegenerative proteinopathies.
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Antocianinas , Factor 2 Relacionado con NF-E2 , Especies Reactivas de Oxígeno , Antocianinas/farmacología , Antocianinas/química , Humanos , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Enfermedades por Prión/tratamiento farmacológico , Enfermedades por Prión/metabolismo , Enfermedades por Prión/patología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Animales , Proteínas PrPSc/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, are identified and characterized by the progressive loss of neurons and neuronal dysfunction, resulting in cognitive and motor impairment. Recent research has shown the importance of PTMs, such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, nitration, truncation, O-GlcNAcylation, and hydroxylation, in the progression of neurodegenerative disorders. PTMs can alter protein structure and function, affecting protein stability, localization, interactions, and enzymatic activity. Aberrant PTMs can lead to protein misfolding and aggregation, impaired degradation, and clearance, and ultimately, to neuronal dysfunction and death. The main objective of this review is to provide an overview of the PTMs involved in neurodegeneration, their underlying mechanisms, methods to isolate PTMs, and the potential therapeutic targets for these disorders. The PTMs discussed in this article include tau phosphorylation, α-synuclein and Huntingtin ubiquitination, histone acetylation and methylation, and RNA modifications. Understanding the role of PTMs in neurodegenerative diseases may provide new therapeutic strategies for these devastating disorders.
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Enfermedad de Alzheimer , Procesamiento Proteico-Postraduccional , Humanos , Fosforilación , Ubiquitinación , AcetilaciónRESUMEN
A new design concept for organic, strongly oxidizing photocatalysts is described based upon dicationic acridinium/carbene hybrids. A highly modular synthesis of such hybrids is presented, and the dications are utilized as novel, tailor-made photoredox catalysts in the direct oxidative C-N coupling. Under optimized conditions, benzene and even electron-deficient arenes can be oxidized and coupled with a range of N-heterocycles in high to excellent yields with a single low-energy photon per catalytic turnover, while commonly used acridinium photocatalysts are not able to perform the challenging oxidation step. In contrast to traditional photocatalysts, the hybrid photocatalysts reported here feature a reversible two-electron redox system with regular or inverted redox potentials for the two-electron transfer. The different oxidation states could be isolated and structurally characterized supported by NMR, EPR, and X-ray analysis. Mechanistic experiments employing time-resolved emission and transient absorption spectroscopy unambiguously reveal the outstanding excited-state potential of our best-performing catalyst (+2.5 V vs SCE), and they provide evidence for mechanistic key steps and intermediates.
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BACKGROUND: Aberrant stress granules (SGs) are emerging as prime suspects in the nucleation of toxic protein aggregates. Understanding the molecular networks linked with aggregation-prone proteins (prion protein, synuclein, and tau) under stressful environments is crucial to understand pathophysiological cascades associated with these proteins. METHODS: We characterized and validated oxidative stress-induced molecular network changes of endogenous aggregation-prone proteins (prion protein, synuclein, and tau) by employing immunoprecipitation coupled with mass spectrometry analysis under basal and oxidative stress conditions. We used two different cell models (SH-SY5Y: human neuroblastoma and HeLa cell line) to induce oxidative stress using a well-known inducer (sodium arsenite) of oxidative stress. RESULTS: Overall, we identified 597 proteins as potential interaction partners. Our comparative interactome mapping provides comprehensive network reorganizations of three aggregation-prone hallmark proteins, establish novel interacting partners and their dysregulation, and validates that prion protein and synuclein localize in cytoplasmic SGs. Localization of prion protein and synuclein in TIA1-positive SGs provides an important link between SG pathobiology and aggregation-prone proteins. In addition, dysregulation (downregulation) of prion protein and exportin-5 protein, and translocation of exportin-5 into the nucleus under oxidative stress shed light on nucleocytoplasmic transport defects during the stress response. CONCLUSIONS: The current study contributes to our understanding of stress-mediated network rearrangements and posttranslational modifications of prion/prion-like proteins. Localization of prion protein and synuclein in the cytoplasmic SGs provides an important link between stress granule pathobiology and aggregation-prone proteins. In addition, our findings demonstrate nucleocytoplasmic transport defects after oxidative stress via dysregulation and nuclear accumulation of exportin-5.
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Sensitized triplet-triplet annihilation upconversion offers an attractive possibility to replace a high-energy photon by two photons with lower energy through the combination of a light-harvesting triplet sensitizer and an annihilator for the formation of a fluorescent singlet state. Typically, high annihilator concentrations are required to achieve an efficient initial energy transfer and as a direct consequence the most highly energetic emission is often not detectable due to intrinsic reabsorption by the annihilator itself. Herein, we demonstrate that the addition of a charge-adapted mediator drastically improves the energy transfer efficiency at low annihilator concentrations via an energy transfer cascade. Inspired by molecular dyads and recent developments in nanocrystal-sensitized upconversion, our system exploits a concept to minimize intrinsic filter effects, while boosting the upconversion quantum yield in solution. A sensitizer-annihilator combination consisting of a ruthenium-based complex and 9,10-diphenylanthracene (DPA) is explored as model system and a sulfonated pyrene serves as mediator. The impact of opposite charges between sensitizer and mediator - to induce coulombic attraction and subsequently result in accelerated energy transfer rate constants - is analyzed in detail by different spectroscopic methods. Ion pairing and the resulting static energy transfer in both directions is a minor process, resulting in an improved overall performance. Finally, the more intense upconverted emission in the presence of the mediator is used to drive two catalytic photoreactions in a two-chamber setup, illustrating the advantages of our approach, in particular for photoreactions requiring oxygen that would interfere with the upconversion system.
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Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (PRNP), in FFI patients with varying ages of onset. Whole-exome sequencing (WES) analysis was performed for twenty-five individuals with FFI (D178N-129M). Gene ontology enrichment analysis was carried out by Reactome to generate hypotheses regarding the biological processes of the identified genes. In the present study, we used a statistical approach tailored to the specifics of the data and identified nineteen potential gene variants with a potential effect on the age of onset. Evidence for potential disease modulatory risk loci was observed in two pseudogenes (NR1H5P, GNA13P1) and three protein coding genes (EXOC1L, SRSF11 and MSANTD3). These genetic variants are absent in FFI patients with early disease onset (19-40 years). The biological function of these genes and PRNP is associated with programmed cell death, caspase-mediated cleavage of cytoskeletal proteins and apoptotic cleavage of cellular proteins. In conclusions, our study provided first evidence for the involvement of genetic risk factors additional to PRNP, which may influence the onset of clinical symptoms in FFI.
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Insomnio Familiar Fatal , Priones , Humanos , Insomnio Familiar Fatal/genética , Secuenciación del Exoma , Edad de Inicio , Genes Reguladores , Proteínas Priónicas/genéticaRESUMEN
Automated detection of lesions using artificial intelligence creates new standards in medical imaging. For people with epilepsy, automated detection of focal cortical dysplasias (FCDs) is widely used because subtle FCDs often escape conventional neuroradiological diagnosis. Accurate recognition of FCDs, however, is of outstanding importance for affected people, as surgical resection of the dysplastic cortex is associated with a high chance of postsurgical seizure freedom. Here, we make publicly available a dataset of 85 people affected by epilepsy due to FCD type II and 85 healthy control persons. We publish 3D-T1 and 3D-FLAIR, manually labeled regions of interest, and carefully selected clinical features. The open presurgery MRI dataset may be used to validate existing automated algorithms of FCD detection as well as to create new approaches. Most importantly, it will enable comparability of already existing approaches and support a more widespread use of automated lesion detection tools.
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Epilepsia , Displasia Cortical Focal , Humanos , Inteligencia Artificial , Epilepsia/diagnóstico por imagen , Epilepsia/cirugía , Displasia Cortical Focal/diagnóstico por imagen , Displasia Cortical Focal/cirugía , Imagen por Resonancia MagnéticaRESUMEN
Amide groups are pervasive across the chemical space continuum, where their structural and pharmacological importance, juxtaposed with the hydrolytic vulnerabilities, continues to fuel bioisostere development. Alkenyl fluorides have a venerable history as effective mimics (Ψ[CF=CH]) owing to the planarity of the motif and intrinsic polarity of the C(sp2 )-F bond. However, emulating the s-cis to the s-trans isomerisation of a peptide bond with fluoro-alkene surrogates remains challenging, and current synthetic solutions only enable access to a single configuration. Through the design of an ambiphilic linchpin based on a fluorinated ß-borylacrylate, it has been possible to leverage energy transfer catalysis to affect this unprecedented isomerisation process: this provides geometrically-programmable building blocks that can be functionalised at either terminus. Irradiation at λmax =402â nm with inexpensive thioxanthone as a photocatalyst enables rapid, effective isomerisation of tri- and tetra-substituted species (up to E/Z 98 : 2 in 1â h), providing a stereodivergent platform for small molecule amide and polyene isostere discovery. Application of the methodology in target synthesis and initial laser spectroscopic studies are disclosed together with crystallographic analyses of representative products.
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α-Synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfolded α-synuclein (αSyn), referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions (Papp-Lantos bodies). Even though the specific cellular distribution of aggregated αSyn differs in PD and DLB patients, both groups show a significant pathological overlap, raising the discussion of whether PD and DLB are the same or different diseases. Besides clinical investigation, we will focus in addition on methodologies, such as protein seeding assays (real-time quaking-induced conversion), to discriminate between different types of α-synucleinopathies. This approach relies on the seeding conversion properties of misfolded αSyn, supporting the hypothesis that different conformers of misfolded αSyn may occur in different types of α-synucleinopathies. Understanding the pathological processes influencing the disease progression and phenotype, provoked by different αSyn conformers, will be important for a personalized medical treatment in future.
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Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Sinucleinopatías , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Sinucleinopatías/diagnóstico , Sinucleinopatías/genética , Sinucleinopatías/metabolismo , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Cuerpos de Lewy/patología , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/genética , Atrofia de Múltiples Sistemas/patologíaRESUMEN
BACKGROUND: Evaluation of the application of CSF real-time quaking-induced conversion in Creutzfeldt-Jakob disease surveillance to investigate test accuracy, influencing factors, and associations with disease incidence. METHODS: In a prospective surveillance study, CSF real-time quaking-induced conversion was performed in patients with clinical suspicion of prion disease (2014-2022). Clinically or histochemically characterized patients with sporadic Creutzfeldt-Jakob disease (n = 888) and patients with final diagnosis of non-prion disease (n = 371) were included for accuracy and association studies. RESULTS: The overall test sensitivity for sporadic Creutzfeldt-Jakob disease was 90% and the specificity 99%. Lower sensitivity was associated with early disease stage (p = 0.029) and longer survival (p < 0.001). The frequency of false positives was significantly higher in patients with inflammatory CNS diseases (3.7%) than in other diagnoses (0.4%, p = 0.027). The incidence increased from 1.7 per million person-years (2006-2017) to 2.0 after the test was added to diagnostic the criteria (2018-2021). CONCLUSION: We validated high diagnostic accuracy of CSF real-time quaking-induced conversion but identified inflammatory brain disease as a potential source of (rare) false-positive results, indicating thorough consideration of this condition in the differential diagnosis of Creutzfeldt-Jakob disease. The surveillance improved after amendment of the diagnostic criteria, whereas the incidence showed no suggestive alterations during the COVID-19 pandemic.
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COVID-19 , Síndrome de Creutzfeldt-Jakob , Humanos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/epidemiología , Estudios Prospectivos , Pandemias , Sensibilidad y EspecificidadRESUMEN
This study aims at the synthesis and initial biological evaluation of novel rhenium-tricarbonyl complexes of 3,3',4',5,7-pentahydroxyflavone (quercetin), 3,7,4Î-trihydroxyflavone (resokaempferol), 5,7-dihydroxyflavone (chrysin) and 4Î,5,7-trihydroxyflavonone (naringenin) as neuroprotective and anti-PrP agents. Resokaempferol was synthesized from 2,2Î,4-trihydroxychalcone by H2O2/NaOH. The rhenium-tricarbonyl complexes of the type fac-[Re(CO)3(Fl)(sol)] were synthesized by reacting the precursor fac-[Re(CO)3(sol)3]+ with an equimolar amount of the flavonoids (Fl) quercetin, resokaempferol, chrysin and naringenin and the solvent (sol) was methanol or water. The respective Re-flavonoid complexes were purified by semi-preparative HPLC and characterized by spectroscopic methods. Furthermore, the structure of Re-chrysin was elucidated by X-ray crystallography. Initial screening of the neuroprotective properties of these compounds included the in vitro assessment of the antioxidant properties by the DPPH assay as well as the anti-lipid peroxidation of linoleic acid in the presence of AAPH and their ability to inhibit soybean lipoxygenase. From the above studies, it was concluded that the complexes' properties are mainly correlated with the structural characteristics and the presence of the flavonoids. The flavonoids and their respective Re-complexes were also tested in vitro for their ability to inhibit the formation and aggregation of the amyloid-like abnormal prion protein, PrPSc, by employing the real-time quaking-induced conversion assay with recombinant PrP seeded with cerebrospinal fluid from patients with Creutzfeldt-Jakob disease. All the compounds blocked de novo abnormal PrP formation and aggregation.
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Antioxidantes , Flavonoides , Proteínas PrPSc , Renio , Humanos , Antioxidantes/farmacología , Cristalografía por Rayos X , Peróxido de Hidrógeno , Quercetina , Renio/química , Flavonoides/química , Flavonoides/farmacología , Proteínas PrPSc/efectos de los fármacos , Proteínas PrPSc/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacologíaRESUMEN
Herein, we describe two complementary approaches towards various organic thiocyanates that are affordable, reliable and follow the principles of sustainable chemistry, starting from commercially available thiols or disulfides. Additionally, the application of this mild method to the first total synthesis of psammaplin B is demonstrated. Non-toxic and inexpensive ferricyanide is used as the cyanide source, which can be activated either in a mechanochemical, solvent-free approach, or in a biphasic solvent system allowing easier work-up. A total of 27 examples is demonstrated, with up to quantitative yields.
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Ferrocianuros , Tiocianatos , Cianuros , DisulfurosRESUMEN
The development of the real-time quaking-induced conversion (RT-QuIC), an in vitro protein misfolding amplification assay, was an innovation in the scientific field of protein misfolding diseases. In prion diseases, these types of assays imitate the pathological conversion of the cellular prion protein (PrPC) into a protease-resistant and/or amyloid form of PrP, called PrP resistant (PrPRes). The RT-QuIC is an automatic assay system based on real-time measuring of thioflavin-T (Th-T) incorporation into amyloid fibrils using shaking for disaggregation. It has already been applied in diagnostics, drug pre-screening, and to distinguish between different prion strains. The seeded conversion efficiency and the diagnostic accuracy of the RT-QuIC assay strongly depend on the kind of recombinant PrP (rec PrP) substrate. The DNA sequences of different substrates may originate from different species, such as human, bank vole, and hamster, or from a combination of two species, e.g., hamster-sheep chimera. In routine use, either full-length (FL) or truncated substrates are applied which can accelerate the conversion reaction, e.g., to a more sensitive version of RT-QuIC assay. In the present review, we provide an overview on the different types of PrP substrates (FL and truncated forms), recapitulate the production and purification process of different rec PrP substrates, and discuss the diagnostic value of CSF RT-QuIC in human prion disease diagnostics.
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Síndrome de Creutzfeldt-Jakob , Priones , Cricetinae , Humanos , Animales , Ovinos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Priones/metabolismo , Proteínas Priónicas/metabolismoRESUMEN
ß-glucocerebrosidase (GBA)-associated mutations are a significant risk factor for Parkinson's disease (PD) that aggravate the disease pathology by upregulating the deposition of α-Synuclein (α-Syn). The resultant clinical profile varies for PD patients without GBA mutations. The current study aimed to identify the proteomic targets involved in the pathogenic pathways leading to the differential clinical presentation of GBA-associated PD. CSF samples (n = 32) were obtained from PD patients with GBA mutations (n = 22), PD patients without GBA mutations (n = 7), and healthy controls that were carriers of GBA mutations (n = 3). All samples were subjected to in-gel tryptic digestion followed by the construction of the spectral library and quantitative SWATH-based analysis. CSF α-Syn levels were reduced in both PDIdiopathic and PDGBA cases. Our SWATH-based mass spectrometric analysis detected 363 proteins involved in immune response, stress response, and cell signaling in various groups. Intergroup analysis showed that 52 proteins were significantly up- or downregulated in various groups. Of these 52 targets, 20 proteins were significantly altered in PDGBA cases only while 2 showed different levels in PDIdiopathic patients. Our results show that the levels of several pathologically relevant proteins, including Contactin-1, Selenium-binding protein 1, Adhesion G Protein-Coupled Receptor, and Apolipoprotein E are significantly different among the sporadic and genetic variants of PD and hint at aggravated synaptic damage, oxidative stress, neuronal loss, and aggregation of α-Syn in PDGBA cases.
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Glucosilceramidasa , Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Espectrometría de Masas , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteoma , Proteómica , Líquido Cefalorraquídeo/química , Líquido Cefalorraquídeo/metabolismoRESUMEN
Long triplet lifetimes of excited photosensitizers are essential for efficient energy transfer reactions in water, given that the concentrations of dissolved oxygen and suitable acceptors in aqueous media are typically much lower than in organic solvents. Herein, we report the design, synthesis and photochemical characterization of two structurally related water-soluble ruthenium complex-based dyads decorated with a covalently attached pyrene chromophore. The triplet energy of the latter is slightly below that of the metal complex enabling a so-called triplet reservoir and excited-state lifetime extensions of up to two orders of magnitude. The diimine co-ligands, which can be modified easily, have a major impact on both the ultrafast intramolecular energy transfer (iEnT) kinetics upon excitation with visible light and the lifetime of the resulting long-lived pyrene triplet. The phenanthroline-containing dyad shows fast triplet pyrene formation (25 ps) and an exceptionally long triplet lifetime beyond 50 microseconds in neat water. The iEnT process via the Dexter mechanism is slower by a factor of two when bipyridine co-ligands are employed, which is rationalized by a poor orbital overlap. Both dyads are very efficient sensitizers for the formation of singlet oxygen in air-saturated water as well as for the bimolecular generation of anthracene triplets that are key intermediates in upconversion mechanisms. This is demonstrated by the 5-hydroxymethylfurfural oxidation, which yields completely different main products depending on the pH value of the aqueous solution, as an initial application-related experiment and by time-resolved spectroscopy. Our findings are important in the greater contexts of photocatalysis and energy conversion in the "green" solvent water.