Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques

Scott, Michael; Foster, Dallas; Mirenda, C.; Serban, Dan; Coufal, Frank; Wälchli, Monika; Torchia, Marilyn; Groth, Darlene; Carlson, George A.; DeArmond, Stephen J.; Westaway, David; Prusiner, Stanley B.

doi:10.1016/0092-8674(89)90608-9

Cited by 659 publications

(356 citation statements)

References 66 publications

Supporting

Mentioning

339

Contrasting

Unclassified

Order By: Relevance

“…Evidence in support of Sp33-37 as an essential (and perhaps the only) structural component of the scrapie agent is substantial and compelling (Bolton et al, 1982(Bolton et al, , 1987aMcKinley et al, 1983;Prusiner et al, 1982aPrusiner et al, , 1990Gabizon et al, 1987Gabizon et al, , 1988Bendheim et al, 1988 b;Carp et al, 1989;Prusiner & McKinley, 1987;Safar et al, 1990;Brown et al, 1990;Scott et al, 1989;Hsiao et al, 1990). The modified-host-protein or protein-only hypothesis of scrapie (Bolton & Bendheim, 1988) has been controversial, however, and a few other studies appear to contradict this interpretation (Czub et al, 1988;Aiken et al, 1989;Sklaviadis et al 1989).…”

Section: Discussionmentioning

confidence: 99%

Copurification of Sp33-37 and Scrapie Agent from Hamster Brain Prior to Detectable Histopathology and Clinical Disease

Bolton¹,

Rudelli²,

Currie³

et al. 1991

Journal of General Virology

View full text Add to dashboard Cite

Studies were conducted to determine whether accumulation of the scrapie agent protein Sp33-37 in brain correlated with the appearance of the scrapie agent or with pathology. The concentrations of the scrapie agent and Sp33-37 were measured in purified fraction P5 isolated from hamster brains at weekly intervals after inoculation. The scrapie agent concentration in fraction P5 was approximately 10 -1 LDs0/g brain 1 day post-inoculation and increased to 10 9.4 LDJg at day 77. Sp33-37 was first detected in P5 at day 21, when the agent titre was 10 3.9 LDs0/g. Sp33-37 concentration increased in concert with the scrapie agent concentration, although the apparent rate of increase was somewhat lower for the protein than for the agent. The histopathological evidence of disease, consisting of mild vacuolation and gliosis, was first seen at 35 days, but was not conspicuous until 49 to 56 days postinoculation. Vacuolation and gliosis increased until termination of the experiment at day 77. Amyloid plaques were first detected at 56 days and were widespread at day 77. Clinical disease was first seen in these animals at day 66, with an average onset at day 71. Control animals inoculated with buffer alone showed some mild gliosis, but were otherwise normal. The fact that Sp33-37 purified with the scrapie agent isolated from brain 14 days prior to detectable (light microscopic) pathology supports the theory that Sp33-37 is the major structural component of the scrapie agent and not solely a product of the pathology.

show abstract

Section: Discussionmentioning

confidence: 99%

Copurification of Sp33-37 and Scrapie Agent from Hamster Brain Prior to Detectable Histopathology and Clinical Disease

Bolton¹,

Rudelli²,

Currie³

et al. 1991

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…In the case of prion transmission from hamsters to mice, this so-called species barrier was overcome by introducing hamster Prnp transgenes into recipient wild-type mice [34,35]. Importantly, the properties of the prions produced in these transgenic mice corresponded to the prion species used for inoculation [35], that is, infection with hamster prions led to production of hamster prions but infection with mouse prions gave rise to mouse prions.…”

Section: Genetic Evidence Linking the Prp Gene With Prion Diseasementioning

confidence: 99%

Molecular biology of transmissible spongiform encephalopathies

1996

View full text Add to dashboard Cite

The prion, the transmissible agent that causes spongiform encephalopathies such as serapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease, is believed to be devoid of nucleic acid and identical with PrP so, a modified form of the normal host protein PrP ¢ which is encoded by the single cop~v gene Prnp. The 'protein only" hypothesis proposes that PrP ~c, when introduced into a normal host, causes the conversion of PrP c into prpS~; it therefore predicts that an animal devoid of PrP c should be resistant to prion diseases. We generated homozygous Prnp °1° ('PrP knockout') mice and showed that, after inoculation with prions, they remained free of scrapie for at least 2 years while wild-type controls all died within 6 months. There was no propagation of prions in the Prnp °t° animals. Surprisingly, heterozygous Prnp °t+ mice, which express PrP c at about half the normal level, also showed enhanced resistance to scrapie disease despite high levels of infectious agent and PrP ~c in the brain early on. After introduction of murine PrP transgenes Prnp °t° mice became highly susceptible to mouse but not to hamster prions, while the insertion of Syrian hamster PrP transgenes rendered them susceptible to hamster but to a much lesser extent to mouse prions. These complementation experiments paved the way to the application of reverse genetics. We have prepared animals transgenic for genes encoding PrP with amino terminal deletions of various lengths and have found that PrP lacking 48 amino proximal amino acids, which comprise four of the five octa repeats of PrP, is still biologically active.

show abstract

“…PS2 cDNA containing a wt human PS2 coding sequence (⌬Glu-235 variant) plus residual 5Ј and 3Ј untranslated sequences, as well as allelic variants differing only at the position of the pathogenic N141I and M239V FAD mutations were independently inserted into a variant (''cosFse1.Tet'') of the hamster PrP cosmid vector cos.Tet (8). This vector includes 25 kb of 5Ј flanking and 10 kb of intronic sequences and engenders position-independent expression (11). PrP gene expression occurs in adult CNS neurons, other adult tissues, and various embryonic structures (17,18).…”

Section: Ps2 Transgenicmentioning

confidence: 99%

Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Mastrangelo

Mathews²,

Chishti³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

␥-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-␤ precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-␤ (A␤) 40 peptide to greater production of A␤42. Although studies in PS1͞PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little A␤40 or A␤42 production, and FAD PS2 alleles support robust production of only A␤42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a ''gained'' competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against ␥-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct ␥-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.

show abstract

Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques

Cited by 659 publications

References 66 publications

Copurification of Sp33-37 and Scrapie Agent from Hamster Brain Prior to Detectable Histopathology and Clinical Disease

Copurification of Sp33-37 and Scrapie Agent from Hamster Brain Prior to Detectable Histopathology and Clinical Disease

Molecular biology of transmissible spongiform encephalopathies

Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Contact Info

Product

Resources

About