Modulation of Creutzfeldt-Jakob disease prion propagation by the A224V mutation

Ann Neurol. 2015 Oct;78(4):540-53. doi: 10.1002/ana.24463. Epub 2015 Aug 25.


Objective: Mutations in the gene encoding the prion protein (PrP) are responsible for approximately 10 to 15% of cases of prion disease in humans, including Creutzfeldt-Jakob disease (CJD). Here, we report on the discovery of a previously unreported C-terminal PrP mutation (A224V) in a CJD patient exhibiting a disease similar to the rare VV1 subtype of sporadic (s) CJD and investigate the role of this mutation in prion replication and transmission.

Methods: We generated transgenic (Tg) mice expressing human PrP with the V129 polymorphism and A224V mutation, denoted Tg(HuPrP,V129,A224V) mice, and inoculated them with different subtypes of sCJD prions.

Results: Transmission of sCJD VV2 or MV2 prions was accelerated in Tg(HuPrP,V129,A224V) mice, compared to Tg(HuPrP,V129) mice, with incubation periods of ∼110 and ∼210 days, respectively. In contrast, sCJD MM1 prions resulted in longer incubation periods in Tg(HuPrP,V129,A224V) mice, compared to Tg(HuPrP,V129) mice (∼320 vs. ∼210 days). Prion strain fidelity was maintained in Tg(HuPrP,V129,A224V) mice inoculated with sCJD VV2 or MM1 prions, despite the altered replication kinetics.

Interpretation: Our results suggest that A224V is a risk factor for prion disease and modulates the transmission behavior of CJD prions in a strain-specific manner, arguing that residues near the C-terminus of PrP are important for controlling the kinetics of prion replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / pathology*
  • Creutzfeldt-Jakob Syndrome / diagnosis*
  • Creutzfeldt-Jakob Syndrome / genetics*
  • Cricetinae
  • Female
  • Humans
  • Mesocricetus
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Mutation / genetics*
  • Peptide Fragments / genetics
  • PrPSc Proteins / genetics*
  • Prions / genetics


  • Peptide Fragments
  • PrPSc Proteins
  • Prions
  • prion protein (125-228), human

Supplementary concepts

  • Creutzfeldt-Jakob Disease, Sporadic