Molecular Mechanisms of Neurodegeneration: Synthetic Prions

Molecular Mechanisms of
Neurodegeneration: Synthetic Prions

Prion diseases, or transmissible spongiform encephalopathies (TSE), are neurodegenerative disorders, which affect human and several animals. The incubation time of these diseases is generally quite long, and once symptoms appear, the diseases progress rapidly, leading to brain damage and death. Till now, prion diseases are invariably fatal with no effective treatment. The causing agent of prion disease is known as prion (acronym for proteinaceous infectious particle), which cause disease within the central nervous system disrupting the normal tissue. Neuropathology of the disease is featured by neuronal loss, gliosis and spongiform changes. The prion protein (PrP) is highly conserved among species. The putative functions of normal cellular form, PrPC and the mechanism of prion replication- a process in which PrPC converts into the pathological form of the prion or PrPSc, have been intensively studied. 

In 2004 the production of synthetic prions via in vitro induction of misfolding and aggregation of bacterially expressed recombinant (rec) PrP was introduced. The material was formed from amyloidal mouse recPrP compose of residues 89-230 of the full-length protein, demonstrating that conversion after polymerization of purified recPrP into amyloidal fibrils, that represent a subset of β sheet-rich structures, is sufficient for the generation of infectivity. The first mouse synthetic prion strain inoculated into transgenic (Tg) 9949 mouse line expressing N-terminal truncated mouse recPrP(89-230) showed clinical disease. Furthermore, brain tissue from these sick mice contained prions that caused TSE disease when inoculated into wild-type mice and Tg mice overexpressing PrP. Neuropathological findings suggested that a novel prion strain was created (see Figure). The incubation time, neuropathological lesion profiles and conformation stability indicated that synthetic prions differ from RML and many other prion strains such as scrapie or bovine spongiform encephalopathy.