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

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

Author information

1
Institute for Neurodegenerative Diseases.
2
Departments of Neurology.
3
Pathology.
4
Pharmaceutical Chemistry.
5
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA.
6
Memory and Aging Center.
7
Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA.

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.

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.

PMID:
26094969
PMCID:
PMC4711268
DOI:
10.1002/ana.24463
[Indexed for MEDLINE]
Free PMC Article

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