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Modulation of C reutzfeldt‐ J akob disease prion propagation by the A 224 V mutation
Author(s) -
Watts Joel C.,
Giles Kurt,
Serban Ana,
Patel Smita,
Oehler Abby,
Bhardwaj Sumita,
Guan Shenheng,
Greicius Michael D.,
Miller Bruce L.,
DeArmond Stephen J.,
Geschwind Michael D.,
Prusiner Stanley B.
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24463
Subject(s) - mutation , creutzfeldt jakob syndrome , genetically modified mouse , virology , incubation period , biology , prion protein , phenotype , disease , pathogenesis , point mutation , transgene , gene , microbiology and biotechnology , incubation , genetics , pathology , medicine , immunology , biochemistry
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. Ann Neurol 2015;78:540–553