Abstract
Prions are unconventional infectious agents that are composed of misfolded aggregated prion protein. Prions replicate their conformation by template-assisted conversion of the endogenous prion protein PrP. Templated conversion of soluble proteins into protein aggregates is also a hallmark of other neurodegenerative diseases. Alzheimer's disease or Parkinson's disease are not considered infectious diseases, although aggregate pathology appears to progress in a stereotypical fashion reminiscent of the spreading behavior ofmammalian prions. While basic principles of prion formation have been studied extensively, it is still unclear what exactly drives PrP molecules into an infectious, self-templating conformation. In this review, we discuss crucial steps in the life cycle of prions that have been revealed in ex vivo models. Importantly, the persistent propagation of prions in mitotically active cells argues that cellular processes are in place that not only allow recruitment of cellular PrP into growing prion aggregates but also enable the multiplication of infectious seeds that are transmitted to daughter cells. Comparison of prions with other protein aggregates demonstrates that not all the characteristics of prions are equally shared by prion-like aggregates. Future experiments may reveal to which extent aggregation-prone proteins associated with other neurodegenerative diseases can copy the replication strategies of prions.
Highlights
Prion diseases or transmissible spongiform encephalopathies (TSEs) are invariably fatal neurodegenerative diseases that are associated with severe spongiform vacuolation and nerve cell loss [1]
Noncell autonomous aggregate induction through external seeds has recently been demonstrated for a variety of different proteins associated with nonprion neurodegenerative diseases
The ability to invade cells and seed cytosolic aggregation appears to be a general feature of amyloidogenic proteins
Summary
Prion diseases or transmissible spongiform encephalopathies (TSEs) are invariably fatal neurodegenerative diseases that are associated with severe spongiform vacuolation and nerve cell loss [1]. PrPSc purified from brains of diseased animals is closely associated with prion infectivity, arguing for a causal relation between the conformational state of the protein and its infectious properties [5]. We will refer to infectious PrP molecules as PrPSc. Propagation of prions is thought to occur through a process of nucleation-dependent polymerization, in which a seed of aggregated PrPSc templates the conformational conversion of its soluble homotypic isoform. Aggregate fragmentation is an essential step in the so-called protein misfolding cyclic amplification (PMCA) developed by Saborio and colleagues [17] In this assay, PrPSc present in brain homogenate serves as a template that is mixed with substrate PrPC present in normal, uninfected brain homogenate. Hsp104 has no homologue in mammalian cells, and the in vivo mechanism of mammalian prion fragmentation is so far unknown
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