title: RuNAway Disease:                              A two cycle model                              for transmissible                              spongiform                              encephalopathies                              (TSEs) wherein                              SINE proliferation                              drives PrP                              overproduction.
abstract: BACKGROUND
  Despite decades of research, the agent responsible for transmitting spongiform encephalopathies (TSEs) has not been identified. The Prion hypothesis, which dominates the field, supposes that modified host PrP protein, termed PrPSc, acts as the transmissible agent. This model fits the observation that TSE diseases elicit almost no immune reaction. Prion transmission has not been verified, however, as it has not been possible to produce pure PrPSc aggregates. One long-standing objection to the Prion model is the observation that TSE disease agents show classical genetic behaviours, such as reproducible strain variation, while also responding to selection for novel traits such as adaptation to new hosts. Moreover, evidence has been steadily accumulating that infectious titre is decoupled from the quantity (or even the presence) of PrPSc deposits. Rather awkwardly for the Prion hypothesis, PrP0/0 knockout mice have been found to incubate and transmit TSE agents (despite themselves being refractory to TSE disease).
  
  
  OBJECTIVE
  In this article, a new scheme, RuNAway, is proposed whereby uncontrolled proliferation of a type of parasitic gene, the small dispersed repeat sequences (SINEs), in somatic cells induces overproduction of PrP with pathogenic consequences. The RuNAway scheme involves twin tandem positive feedback loops: triggering the second loop leads to the pathogenic disease. This model is consistent with the long latency period and much shorter visible disease progression typical of TSEs.
authors.affiliation: European Molecular Biology Laboratory, Postfach 10.2209, 69012 Heidelberg, Germany. Toby.Gibson@EMBL-Heidelberg.de
authors.forename: T J
authors.initials: TJ
authors.lastname: Gibson
mesh_terms: D000818:Animals; D007562:Creutzfeldt-Jakob Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D018620:PrPSc Proteins / Q000235:genetics* / Q000378:metabolism; D020086:Short Interspersed Nucleotide Elements / Q000235:genetics*
chemical_list: D018620:PrPSc Proteins