Transmission of prions

Weissmann, Charles; Enari, Masato; Klöhn, Peter-Christian; Rossi, Daniela; Flechsig, Eckhard

doi:10.1073/pnas.172403799

Cited by 124 publications

(47 citation statements)

References 86 publications

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“…C2 was also detected in glycosidase-treated brain extracts from Syrian hamsters infected with the Sc237 strain of prions. 2 The ϳ17-kDa PK-sensitive C-terminal PrP fragment, present in uninfected and RMLinfected mouse brain extracts (Fig. 2a), corresponds to the PrP C -specific cleavage product C1 fragment previously identified in human brain extracts (1).…”

Section: Prp C and Prp Sc Are Cleaved By Endogenous Proteases In Braimentioning

confidence: 55%

“…During the disease process, PrP Sc acts as a template for conversion by imposing its conformation on the normally benign host-encoded version of the prion protein referred to as PrP C (reviewed in Ref. 2). The conversion of PrP C into PrP Sc involves a profound conformational change: PrP C has a high ␣-helical content and is virtually devoid of ␤-sheet while PrP Sc has high ␤-sheet content (3)(4)(5).…”

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confidence: 99%

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Calpain-dependent Endoproteolytic Cleavage of PrPSc Modulates Scrapie Prion Propagation

Rajgopal

Guttmann

Seward

et al. 2004

Journal of Biological Chemistry

113

116

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Previous studies using post-mortem human brain extracts demonstrated that PrP in Creutzfeldt-Jakob disease (CJD) brains is cleaved by a cellular protease to generate a C-terminal fragment, referred to as C2, which has the same molecular weight as PrP-(27-30), the protease-resistant core of PrP Sc (1). The role of this endoproteolytic cleavage of PrP in prion pathogenesis and the identity of the cellular protease responsible for production of the C2 cleavage product has not been explored. To address these issues we have taken a combination of pharmacological and genetic approaches using persistently infected scrapie mouse brain (SMB) cells. We confirm that production of C2 is the predominant cleavage event of PrP Sc in the brains of scrapieinfected mice and that SMB cells faithfully recapitulate the diverse intracellular proteolytic processing events of PrP Sc and PrP C observed in vivo. While increases in intracellular calcium (Ca 2؉ ) levels in prion-infected cell cultures stimulate the production of the PrP Sc cleavage product, pharmacological inhibitors of calpains and overexpression of the endogenous calpain inhibitor, calpastatin, prevent the production of C2. In contrast, inhibitors of lysosomal proteases, caspases, and the proteasome have no effect on C2 production in SMB cells. Calpain inhibition also prevents the accumulation of PrP Sc in SMB and persistently infected ScN2A cells, whereas bioassay of inhibitor-treated cell cultures demonstrates that calpain inhibition results in reduced prion titers compared with control-treated cultures assessed in parallel. Our observations suggest that calpain-mediated endoproteolytic cleavage of PrP Sc may be an important event in prion propagation.

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Section: Prp C and Prp Sc Are Cleaved By Endogenous Proteases In Braimentioning

confidence: 55%

mentioning

confidence: 99%

Calpain-dependent Endoproteolytic Cleavage of PrPSc Modulates Scrapie Prion Propagation

Rajgopal

Guttmann

Seward

et al. 2004

Journal of Biological Chemistry

113

116

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“…In mammals, ''vegetative'' prion transmission by ingestion or infection has been observed to propagate prion diseases (35). In this study, we have demonstrated that, in the nonisogamously mating fungus P. anserina, prions of maternal origin are transmitted through a sexual pathway resulting in meiotic drive, with potential consequences for the level of prion infection in Podospora populations.…”

Section: Discussionmentioning

confidence: 73%

Sexual transmission of the [Het-s] prion leads to meiotic drive in Podospora anserina

Dalstra

Swart²,

Debets³

et al. 2003

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

102

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In the filamentous fungus Podospora anserina, two phenomena are associated with polymorphism at the het-s locus, vegetative incompatibility and ascospore abortion. Two het-s alleles occur naturally, het-s and het-S. The het-s encoded protein is a prion propagating as a self-perpetuating amyloid aggregate. M eiotic drive is a process mediated by genetic elements, called segregation distorters, that actively bias Mendelian segregation in their favor. In metazoans, classic examples of meiotic drive include the t haplotype in mice and Segregation Distorter (SD) in Drosophila (1). In both these autosomal drive systems, heterozygous males produce gametes of the driver genotype in excess. The molecular mechanisms of meiotic drive remain largely elusive, except in the case of SD in Drosophila, where distortion involves a truncated form of a RanGAP protein and its mislocalization to the nucleus (2). The best studied examples of segregation distortion in fungi are the spore killer systems in the ascomycetes Neurospora crassa (3-6) and Podospora anserina (7). In these haploid organisms, the sexual progeny, the ascospores, are linearly arranged after meiosis. Ascomycetes therefore provide excellent opportunities to investigate the behavior of meiotic drive elements (8). Presence of a killer gene can readily be detected by directly analyzing the pattern of ascospore abortion. Spore killer genes exist as a killer and a sensitive allele or haplotype. In a killer ϫ sensitive cross, the ascospores harboring only the sensitive genotype degenerate. Heterokaryotic spores, containing both a sensitive and a killer nucleus, escape abortion. Both in Neurospora and in Podospora, several spore killer loci have been genetically identified, but so far the mechanism of spore killing is unknown.In 1965, Bernet (9, 10) described properties of the het-s gene in Podospora, now recognized to be analogous to a spore killer locus. The discovery that het-s encodes a prion protein (11, 12) places this observation into a new perspective. The het-s locus, together with at least eight other loci, determines vegetative incompatibility in P. anserina (13,14). Two alleles are found at this locus, termed het-s During the sexual cycle, a single mating-type culture of P. anserina differentiates both male (microconidia) and female (protoperithecia) reproductive structures. The protoperithecium emits a specialized hypha called the trichogyne. Fertilization occurs when a microconidium fuses with a trichogyne of opposite mating type. After migration of the male nucleus down the trichogyne into the female ascogonium, individualized male and female nuclei divide synchronously in a syncytial structure. Because the male gamete contributes very little cytoplasm to this heterokaryon, the cytoplasm of the zygote is essentially of maternal origin. Nuclei of opposite mating type then pair up, and karyogamy takes place in specialized cells. Importantly, at this stage there is a transition from a syncytial to a cellular state (21). Meiotic progeny are linearly arranged as ...

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“…'' Considerable evidence supports a prion basis for the transmissible spongiform encephalopathies (TSEs) of mammals, with an amyloid form of the PrP protein as the culprit (1). The gene for PrP controls the clinical and pathological features of the TSEs (2-7).…”

mentioning

confidence: 99%

Conservation of a portion of the S. cerevisiae Ure2p prion domain that interacts with the full-length protein

Edskes

Wickner

2002

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

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Transmission of prions

Cited by 124 publications

References 86 publications

Calpain-dependent Endoproteolytic Cleavage of PrPSc Modulates Scrapie Prion Propagation

Calpain-dependent Endoproteolytic Cleavage of PrPSc Modulates Scrapie Prion Propagation

Sexual transmission of the [Het-s] prion leads to meiotic drive in Podospora anserina

Conservation of a portion of the S. cerevisiae Ure2p prion domain that interacts with the full-length protein

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