Aggregated, wild-type prion protein causes neurological dysfunction and synaptic abnormalities

Roberto Chiesa, Pedro Piccardo, Emiliano Biasini, Bernardino Ghetti, David A. Harris

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The neurotoxic forms of the prion protein (PrP) that cause neurodegeneration in prion diseases remain to be conclusively identified. Considerable evidence points to the importance of noninfectious oligomers of PrP in the pathogenic process. In this study, we describe lines of Tg(WT) transgenic mice that over-express wild-type PrP by either ∼5-fold or ∼10-fold (depending on whether the transgene array is, respectively, hemizygous or homozygous). Homozygous but not hemizygous Tg(WT) mice develop a spontaneous neurodegenerative illness characterized clinically by tremor and paresis. Both kinds of mice accumulate large numbers of punctate PrP deposits in the molecular layer of the cerebellum as well as in several other brain regions, and they display abnormally enlarged synaptic terminals accompanied by a dramatic proliferation of membranous structures. The over-expressed PrP in Tg(WT) mice assembles into an insoluble form that is mildly protease-resistant and is recognizable by aggregation-specific antibodies, but that is not infectious in transmission experiments. Together, our results demonstrate that noninfectious aggregates of wild-type PrP are neurotoxic, particularly to synapses, and they suggest common pathogenic mechanisms shared by prion diseases and nontransmissible neurodegenerative disorders associated with protein misfolding.

Original languageEnglish (US)
Pages (from-to)13258-13267
Number of pages10
JournalJournal of Neuroscience
Volume28
Issue number49
DOIs
StatePublished - Dec 3 2008

Keywords

  • Neurodegeneration
  • Prion
  • Protein aggregation
  • Synapse
  • Transgenic
  • Wild-type

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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