| Summary |
Transmissible spongiform encephalopathies (TSEs) are often propagated by extracerebral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex. While lymphatic organs show early accumulation of prions, B-cells and follicular dendritic cells are required for efficient neuroinvasion. Intact prions enter the central nervous system probably via peripheral nerves and may need a cellular counterpart of prion protein (PrPC) for propagation. TSEs are characterized by accumulating an abnormal isoform (PrPSc) of the host-encoded PrPC in brain. In 1982, Prusiner firstly purified the infectious agent from hamster brain and introduced the term “prion” for
proteinaceous infectious particle. The PrP isoforms contain identical amino-acid sequence, yet differ in their overall secondary structure with the PrPSc isoform,possess a higher β-sheet and lower α-helix content than PrPC. In 1967, Griffith suggested that the possible cause of scrapie may be a self-replicating protein.
Consequently, by a series of experiments, Prusiner et al. demonstrated that the infectivity was increased when a specific protein was contained in the sample. In the other words, the infectivity correlated closely with the concentration of the protein.According to these results, Prusiner proposed and developed the “protein-only”hypothesis. Weissmann et al. cloned and sequenced the host PrP gene, which encodes for PrPC. By unknown mechanisms, an autocatalytic cycle was probably initiated by introducing exogenous PrPSc, and resulted in the conversion of a-helix intoβ-sheet conformation. Unlike the a-helical PrPC, the protease-resistant core of PrPSc is predominantly b-sheet and possesses a tendency to polymerize into amyloid fibrils.Nevertheless, the molecular mechanism of the conformation rearrangement of PrPC into PrPSc is still unknown.
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