Abstract
The prion hypothesis postulates that the infectious agent in transmissible spongiform encephalopathies (TSEs) is an unorthodox protein conformation based agent. Recent successes in generating mammalian prions in vitro with bacterially expressed recombinant prion protein provide strong support for the hypothesis. However, whether the pathogenic properties of synthetically generated prion (rec-Prion) recapitulate those of naturally occurring prions remains unresolved. Using end-point titration assay, we showed that the in vitro prepared rec-Prions have infectious titers of around 104 LD50 / μg. In addition, intraperitoneal (i.p.) inoculation of wild-type mice with rec-Prion caused prion disease with an average survival time of 210 – 220 days post inoculation. Detailed pathological analyses revealed that the nature of rec-Prion induced lesions, including spongiform change, disease specific prion protein accumulation (PrP-d) and the PrP-d dissemination amongst lymphoid and peripheral nervous system tissues, the route and mechanisms of neuroinvasion were all typical of classical rodent prions. Our results revealed that, similar to naturally occurring prions, the rec-Prion has a titratable infectivity and is capable of causing prion disease via routes other than direct intra-cerebral challenge. More importantly, our results established that the rec-Prion caused disease is pathogenically and pathologically identical to naturally occurring contagious TSEs, supporting the concept that a conformationally altered protein agent is responsible for the infectivity in TSEs.
Highlights
Transmissible Spongiform Encephalopathies (TSEs, known as prion diseases) are fatal transmissible neurodegenerative disorders, which include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans [1,2]
The prion hypothesis postulates that prions are protein conformation based infectious agents responsible for transmissible spongiform encephalopathies (TSEs)
Prions have been synthetically generated in vitro, but it remains unclear whether the properties of synthetically generated prion are the same as those of TSE agents and whether the disease caused by synthetically generated prion is identical to naturally occurring TSEs
Summary
Transmissible Spongiform Encephalopathies (TSEs, known as prion diseases) are fatal transmissible neurodegenerative disorders, which include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans [1,2]. The development of more sensitive assays, such as the conformation-dependent immunoassay (CDI) [10], or antibodies recognizing diseased PrP conformers, such as 15B3 antibody [11,12], led to the discovery of various PrP conformers in the diseased brains that are distinct from PrPC [13,14] Some of these PrP conformers are completely sensitive to PK digestion [13,14,15,16] and it was estimated that up to 90% of the disease specific PrP conformers in sporadic CJD cases are PK sensitive PrP conformers [13]. These findings are consistent with the notion that PrP is able to exist in multiple thermodynamically stable conformations [17,18,19] either by itself or by forming complex with other factors, but whether only one or multiple of these PrP conformers are associated with the prion infectivity remains unclear
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