Prions are the causative agent of fatal neurodegenerative diseases that affect humans and other mammalian species, known as transmissible spongiform encephalopathies (TSEs). They are proteins that present several isoforms displaying different conformations, and at least one of which has the capacity to self-replicate. Although the initial mechanisms remain poorly understood, a conformational change occurs in the initial phases of the disease that leads to the conversion of the physiological cellular prion protein (PrPC) into a pathogenic misfolded isoform, designated PrPSc. The later acts as a template, transforming newly synthesized PrPC into PrPSc, thus propagating itself within the hosts’ tissues. The precise atomic structure of PrPC is well established, being a rich a-helix structure protein. Contrarily, PrPSc has a higher content of ß-sheet structures and tends to aggregate and form oligomers. Recent evidence suggests it is a 4-rung ß-solenoid and a physically plausible, stable atomic model of it has been built. According to the Anfinsen’s hypothesis, PrPC is the native conformation. However, it is a kinetically trapped conformer, whereas the PrPSc amyloid is kinetically hampered but thermodynamically more stable. Different PrPSc isoforms, or prion strains, differ in conformation, glycosylation, as well as in the sizes of the fragments resistant to proteinase K (PK) digestion, being responsible for a specific disease phenotype.
Infective prions can spread among different hosts of the same species and, although a species barrier exists in some TSEs, the possibility of PrPSc spreading between hosts of different species is attested for several TSEs. It was already demonstrated that PrPSc can be present in blood or in excretions like urine, feces or saliva of infected human and animals, which together with the ability for prions to persist in the environment during long periods of time, poses a serious public health problem. Recent studies have focused on in vivo diagnostic tools that allow the detection of pre-clinical stages of the disease, the majority of which are based on the prion amplification strategy: the protein misfolding cycling amplification (PMCA) and the real time quaking-induced conversion assay (RT- QuIC). In both methods, a cyclical, coerced conversion of normal cellular or recombinant prion protein into the misfolded isoform is performed. As these methods are being adopted worldwide in laboratories devoted to prion research and diagnosis, it is important to bear in mind that the final products of PMCA are infectious, whereas no infectivity has been ascribed to date to RT-QuIC products. In any case, it is of pivotal importance to perform additional studies in order to address the biosafety of the final reaction products.
With this Research Topic we invite contributors to share cutting edge investigation aiming to improve the knowledge of PrPSc molecular structure, focusing on the mechanisms underlying its abnormal folding, as well as on biomarkers for early detection of PrPSc and PrPC stabilization in infected humans and animals. Studies on PrPSc final reaction products' infectivity and the development of innovative techniques on PrPSc inactivation are also welcomed.
Articles can be submitted in the form of original research, review, mini-review, opinion and case report. Articles based on oral and poster presentations at the 8th Iberian Congress on Prions are encouraged.
Prions are the causative agent of fatal neurodegenerative diseases that affect humans and other mammalian species, known as transmissible spongiform encephalopathies (TSEs). They are proteins that present several isoforms displaying different conformations, and at least one of which has the capacity to self-replicate. Although the initial mechanisms remain poorly understood, a conformational change occurs in the initial phases of the disease that leads to the conversion of the physiological cellular prion protein (PrPC) into a pathogenic misfolded isoform, designated PrPSc. The later acts as a template, transforming newly synthesized PrPC into PrPSc, thus propagating itself within the hosts’ tissues. The precise atomic structure of PrPC is well established, being a rich a-helix structure protein. Contrarily, PrPSc has a higher content of ß-sheet structures and tends to aggregate and form oligomers. Recent evidence suggests it is a 4-rung ß-solenoid and a physically plausible, stable atomic model of it has been built. According to the Anfinsen’s hypothesis, PrPC is the native conformation. However, it is a kinetically trapped conformer, whereas the PrPSc amyloid is kinetically hampered but thermodynamically more stable. Different PrPSc isoforms, or prion strains, differ in conformation, glycosylation, as well as in the sizes of the fragments resistant to proteinase K (PK) digestion, being responsible for a specific disease phenotype.
Infective prions can spread among different hosts of the same species and, although a species barrier exists in some TSEs, the possibility of PrPSc spreading between hosts of different species is attested for several TSEs. It was already demonstrated that PrPSc can be present in blood or in excretions like urine, feces or saliva of infected human and animals, which together with the ability for prions to persist in the environment during long periods of time, poses a serious public health problem. Recent studies have focused on in vivo diagnostic tools that allow the detection of pre-clinical stages of the disease, the majority of which are based on the prion amplification strategy: the protein misfolding cycling amplification (PMCA) and the real time quaking-induced conversion assay (RT- QuIC). In both methods, a cyclical, coerced conversion of normal cellular or recombinant prion protein into the misfolded isoform is performed. As these methods are being adopted worldwide in laboratories devoted to prion research and diagnosis, it is important to bear in mind that the final products of PMCA are infectious, whereas no infectivity has been ascribed to date to RT-QuIC products. In any case, it is of pivotal importance to perform additional studies in order to address the biosafety of the final reaction products.
With this Research Topic we invite contributors to share cutting edge investigation aiming to improve the knowledge of PrPSc molecular structure, focusing on the mechanisms underlying its abnormal folding, as well as on biomarkers for early detection of PrPSc and PrPC stabilization in infected humans and animals. Studies on PrPSc final reaction products' infectivity and the development of innovative techniques on PrPSc inactivation are also welcomed.
Articles can be submitted in the form of original research, review, mini-review, opinion and case report. Articles based on oral and poster presentations at the 8th Iberian Congress on Prions are encouraged.
