title: Modulation of Creutzfeldt-Jakob disease prion propagation by the A224V mutation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Neurodegenerative Diseases.|Departments of Neurology.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Watts
authors.affiliation: Institute for Neurodegenerative Diseases.|Departments of Neurology.
authors.forename: Kurt
authors.initials: K
authors.lastname: Giles
authors.affiliation: Institute for Neurodegenerative Diseases.
authors.forename: Ana
authors.initials: A
authors.lastname: Serban
authors.affiliation: Institute for Neurodegenerative Diseases.
authors.forename: Smita
authors.initials: S
authors.lastname: Patel
authors.affiliation: Pathology.
authors.forename: Abby
authors.initials: A
authors.lastname: Oehler
authors.affiliation: Institute for Neurodegenerative Diseases.
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhardwaj
authors.affiliation: Institute for Neurodegenerative Diseases.|Pharmaceutical Chemistry.
authors.forename: Shenheng
authors.initials: S
authors.lastname: Guan
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Greicius
authors.affiliation: Memory and Aging Center.|Departments of Neurology.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Institute for Neurodegenerative Diseases.|Pathology.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.affiliation: Memory and Aging Center.|Departments of Neurology.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
authors.affiliation: Institute for Neurodegenerative Diseases.|Departments of Neurology.|Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis* / Q000235:genetics*; D006224:Cricetinae; D005260:Female; D006801:Humans; D008647:Mesocricetus; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000235:genetics; D018620:PrPSc Proteins / Q000235:genetics*; D011328:Prions / Q000235:genetics
chemical_list: D010446:Peptide Fragments; D018620:PrPSc Proteins; D011328:Prions; C512259:prion protein (125-228), human