Abstract
The misfolding of the cellular prion protein (PrPC) into the disease-associated isoform (PrPSc) and its accumulation as amyloid fibrils in the central nervous system is one of the central events in transmissible spongiform encephalopathies (TSEs). Due to the proteinaceous nature of the causal agent the molecular mechanisms of misfolding, interspecies transmission, neurotoxicity and strain phenomenon remain mostly ill-defined or unknown. Significant advances were made using in vivo and in cellula models, but the limitations of these, primarily due to their inherent complexity and the small amounts of PrPSc that can be obtained, gave rise to the necessity of new model systems. The production of recombinant PrP using E. coli and subsequent induction of misfolding to the aberrant isoform using different techniques paved the way for the development of cell-free systems that complement the previous models. The generation of the first infectious recombinant prion proteins with identical properties of brain-derived PrPSc increased the value of cell-free systems for research on TSEs. The versatility and ease of implementation of these models have made them invaluable for the study of the molecular mechanisms of prion formation and propagation, and have enabled improvements in diagnosis, high-throughput screening of putative anti-prion compounds and the design of novel therapeutic strategies. Here, we provide an overview of the resultant advances in the prion field due to the development of recombinant PrP and its use in cell-free systems.
Highlights
Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders which have in common the formation of amyloid plaques due to the accumulation of prion protein (PrP) which has been converted to an abnormal conformation, known as PrPSc, in the central nervous system (CNS)
Five different prion diseases have been reported to date: Kuru [2], Gerstmann-Straüssler-Scheinker Syndrome (GSS) [3], Fatal Familial Insomnia (FFI) [4], Creutzfeldt-Jakob Disease (CJD) [5] and Variably Protease-sensitive Prionopathy (VPSPr) [6]
Compelling evidence has been gathered in support of the protein-only hypothesis of prion disease [13,14] resulting in the proteinaceous nature of the etiologic agent of transmissible spongiform encephalopathies (TSEs) accepted widely
Summary
Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders which have in common the formation of amyloid plaques due to the accumulation of prion protein (PrP) which has been converted to an abnormal conformation, known as PrPSc , in the central nervous system (CNS). Some of the problems associated with in vivo and in cellula models, primarily the limited quantity of PrPSc that could be obtained, were overcome in 1997 when Wüthrich and collaborators developed a novel technique to generate large amounts of recombinant PrP (rec-PrP) in Escherichia coli using a nickel-based purification system [41] This technique enables the production of highly concentrated and pure rec-PrP for use in further investigations and has already proven its value in the study of TSEs. Despite the differences between brain-derived and recombinant PrP (the latter lacks glycosylations and GPI-anchoring to the cell membrane), it has enabled the atomic structure of the non-pathogenic. We focus on the different uses of rec-PrP and infectious misfolded rec-PrP and how their development has been pivotal in the field of TSE by enabling: mechanistic and structural studies, improvements in diagnosis and high-throughput screening of anti-prion compounds and the design of new therapeutic strategies (Table 1)
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