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Micronutrients in the Management of Prion Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
The mechanisms of neurotoxicity are highly complex; therefore, in vitro models using toxic prion peptides have been used to study this. Prion peptide PrP106-126 peptide that induces neuropathology similar to that of PrPsc appears to produce neurotoxicity by multiple pathways. It activates microglia that release reactive oxygen species (ROS) and pro-inflammatory cytokines.63 It also increases Ca2+ uptake through voltage-sensitive Ca2+ channels, and thus activates NMDA receptors leading to cell death.64 Other mechanisms of toxicity were investigated by generating the β-sheet state of oligomeric PrPsc through protein misfolding cyclic amplification from recombinant full-length in hamster, human, rabbit, and mutated rabbit PrPc. These β-sheet oligomers are toxic to primary mouse cortical neurons independent of the presence of PrPc in the neurons. The mechanisms of toxicity produced by these beta-oligomers involve elevation of levels of proapoptotic proteins such as Bcl2, Bax, and caspase-3.65 Another mechanism was suggested by the beta-amyloid of Alzheimer’s disease that has beta-sheet configuration similar to that of PrPsc. This is suspected to cause neuronal death by generation of prooxidant free radicals.66–68 It is likely that PrPsc-induced prion aggregates also induce neuronal death by this mechanism. This is further substantiated by reports, to be discussed in the subsequent section, in which antioxidants prevent the progression of prion diseases in both cell culture and intact animals.
Prions
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Currently, there are two main models describing the conversion from PrPC to PrPSc; namely, the refolding and seeding models [9]. The refolding model proposes that a single particle of endogenous PrPC interacts with exogenously introduced PrPSc to generate more PrPSc. The seeding model proposes that PrPSc exists in equilibrium with PrPC. In healthy individuals, this equilibrium favors PrPC, thereby resulting in an absence of prion disease. By contrast, an oligomer or short polymers of PrPSc can interact with PrP to form an infectious unit. The seeding model is supported by PMCA (protein misfolding cyclic amplification), which mimics the autocatalytic replication of PrPSc [15]. PMCA is analogous to the polymerase chain reaction (PCR) methodology that is used to amplify DNA. During PMCA, the destruction of PrPSc aggregates causes fragmentation of infectious seed in the sonication process, which can drive the conversion of PrPC to yield more PrPSc. The generated infectious particles amplified by PMCA retain infectivity [16]. In addition, PK-resistant PrP (PrPres) generated by PMCA shows physicochemical and structural properties similar to those of PrPres derived from infected brains [16].
A Clinical Incident Linked to Prion-Associated Disease
Published in Meera Chand, John Holton, Case Studies in Infection Control, 2018
The first step in this incident is to establish the level of certainty regarding the diagnosis in the index case and ascertain what sort of prion disease is likely to be involved. Diagnosis of probable CJD is based primarily on clinical presentation. Laboratory investigation is used to exclude other causes as well as to detect the surrogate marker, the 14-3-3 protein in the cerebrospinal fluid (CSF). There are also assays for the direct detection of PrPSc in the CSF, including protein misfolding cyclic amplification (PMCA) assay and real-time quaking-induced conversion (RT-QUIC). More recently, aggregation of gold nanoparticles by beta-pleated sheet proteins had been used to detect prion proteins in the CSF. Confirmation is provided by histopathological and immunological investigation of brain tissue. Brain biopsies are rarely undertaken during life as they will usually not affect prognosis, and, as the changes are diffuse, a biopsy may miss the relevant area. Confirmation may therefore be post mortem. The classical histopathological features are neuronal loss, spongiform changes, and astrocytic gliosis. In addition, the use of antibodies 3F4 and KG9 provide immunohistochemical confirmation. If a diagnosis of prion disease is possible, it is necessary to assess the risk from the tissues involved in the surgery. Quarantine any reusable instruments pending confirmation of the diagnosis. Prior to storage, the instruments should be decontaminated. Determine the fate of any disposable instruments and confirm if they were incinerated.
Ultrasensitive techniques and protein misfolding amplification assays for biomarker-guided reconceptualization of Alzheimer’s and other neurodegenerative diseases
Published in Expert Review of Neurotherapeutics, 2021
Nicole Campese, Maria Francesca Beatino, Claudia Del Gamba, Elisabetta Belli, Linda Giampietri, Eleonora Del Prete, Alessandro Galgani, Andrea Vergallo, Gabriele Siciliano, Roberto Ceravolo, Harald Hampel, Filippo Baldacci
To identify articles addressing the role of seeding amplification assays in the workup of NDDs we used the following combination of keywords: ((‘cerebrospinal fluid’ OR ‘CSF’) AND (‘protein misfolding cyclic amplification’ OR ‘PMCA’)), ((‘cerebrospinal fluid’ OR ‘CSF’) AND (‘RT-QuIC’ OR ‘Real Time Quaking Induced Conversion’)), ((‘blood’ OR ‘plasma’) AND (‘RT-QuIC’ OR ‘Real Time Quaking Induced Conversion’)) and ((‘blood’ OR ‘plasma’) AND (‘protein misfolding cyclic amplification’ OR ‘PMCA’)). Papers published between January 2010 and June 2021 were included. A total of 545 papers were screened and 19 were retained for the final analysis. Since no papers on blood or plasma were identified, only papers addressing the diagnostic and prognostic performance of RT-QuIC or PMCA in CSF were included.
Tackling prion diseases: a review of the patent landscape
Published in Expert Opinion on Therapeutic Patents, 2021
Marco Zattoni, Giuseppe Legname
Recent advances in prion research have led to the development of novel and accurate prion detection methods, which have been introduced among the various tools useful for the validation of putative therapeutic approaches. With the advent of the Protein Misfolding Cyclic Amplification (PMCA), thanks to the use of cyclic sonication and incubation steps, even low traces of PrPSc can be detected using standard WB technique [20,21]. Real Time Quaking-Induced Conversion (RT-QuIC) assay, recently introduced among the diagnostic criteria for the probable diagnosis of sCJD, uses shaking in the absence of sonication, recombinant PrP (recPrP) instead of brain homogenate as substrate for PrPSc amplification, and a thioflavin T (ThT)-based detection method [22,23].