Surabhi Bhardwaj

© 2015 The Author. Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice infected with prions that caused scrapie in sheep or prions that caused chronic wasting disease in deer, using 2 isolates for each disease. IND24 doubled the incubation times for mice infected with CWD prions but had no effect on the survival of those infected with scrapie prions. Biochemical, neuropathologic, and cell culture analyses were used to characterize prion strain properties following treatment, and results indicated that the CWD prions were not altered by IND24, regardless of survival extension. These results suggest that IND24 may be a viable candidate for treating CWD in infected captive cervid populations and raise questions about why some prion strains develop drug resistance whereas others do not.

© 2015 American Neurological Association. Objective Mutations in the gene encoding the prion protein are responsible for approximately 10 to 15% of cases of prion disease in humans, including Creutzfeldt-Jakob disease. Here, we report on the discovery of a previously unreported C-terminal PrP mutation in a CJD patient exhibiting a disease similar to the rare VV1 subtype of sporadic CJD and investigate the role of this mutation in prion replication and transmission. Methods We generated transgenic mice expressing human PrP with the V129 polymorphism and A224V mutation, denoted Tg mice, and inoculated them with different subtypes of sCJD prions. Results Transmission of sCJD VV2 or MV2 prions was accelerated in Tg mice, compared to Tg mice, with incubation periods of ∼110 and ∼210 days, respectively. In contrast, sCJD MM1 prions resulted in longer incubation periods in Tg mice, compared to Tg mice. Prion strain fidelity was maintained in Tg 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.