A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy

Abstract

A mutation equivalent to P102L in the human PrP gene, associated with Gerstmann-Straussler syndrome (GSS), has been introduced into the murine PrP gene by gene targeting. Mice homozygous for this mutation (101LL) showed no spontaneous transmissible spongiform encephalopathy (TSE) disease, but had incubation times dramatically different from wild-type mice following inoculation with different TSE sources. Inoculation with GSS produced disease in 101LL mice in 288 days. Disease was transmitted from these mice to both wild-type (226 days) and 101LL mice (148 days). In contrast, 101LL mice infected with ME7 had prolonged incubation times (338 days) compared with wild-type mice (161 days). The 101L mutation does not, therefore, produce any spontaneous genetic disease in mice but significantly alters the incubation time of TSE infection. Additionally, a rapid TSE transmission was demonstrated despite extremely low levels of disease-associated PrP.

Altered Glycosylated PrP Proteins Can Have Different Neuronal Trafficking in Brain but Do Not Acquire Scrapie-like Properties

“…Targeted ES cells were used to generate chimeric mice as described previously (25) to obtain G1 and G2 heterozygous mice expressing mono-and unglycosylated PrP and G3 heterozygous mice expressing unglycosylated PrP. Heterozygous mice were bred to produce an inbred homozygous line.…”

De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

“…Some of these genetic diseases have been transmitted to primates or mice (6,7). De novo production of infectious prions from PRNP with point mutations would represent a useful tool for elucidating the origin of prion infectivity in genetic TSEs.…”

Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

“…Previous studies argued about a lack of correspondence between infectivity titers or disease severity and amount of PK-resistant PrP Sc . 18,19 In particular, Barron and coworkers demonstrated that tissues with very low levels of PK-resistant PrP Sc could be highly infective. 20 In this regard, the expression of scFvD18 could have hampered the formation of PK-resistant PrP Sc without interfering with an alternative PK-sensitive PrP Sc isoform.…”