Insertions in the prion protein gene in atypical dementias

Owen, F.; Poulter, Mark; Collinge, John; Leach, M.; Shah, T.; Lofthouse, R.; Chen, Yanfang; Crow, T. J.; Harding, A. E.; Hardy, John; Rossor, Martin N.

doi:10.1016/0014-4886(91)90075-n

Cited by 41 publications

(14 citation statements)

References 11 publications

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“…The formation of PrPsr from PrPC or a precursor with one, two, four, or six additional ORs in ScN2a cells was similar to that observed for wt PrP. In families with the inherited Creutzfeldt-Jakob disease, affected members have four to nine ORs in addition to the five ORs found in wt PrP (17)(18)(19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 70%

Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells.

Rogers

Yehiely

Scott

et al. 1993

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

166

122

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The only known component of the infectious prion is a posttranslationafly modified protein known as the scrapie isoform of the prion protein, PrP&. Upon limited proteolysis, a protease-resistant fragment designated PrP 27-30 is formed. Using in vitro mutagenesis, we examined the role of the N and C termini in the formation of prP& in persistently infected, mouse neuroblastoma (ScN2a) cells. Neither deletion of amino acids 23-88, which are also removed by proteinase K in the formation of PrP 27-30, nor deletion of the five octapeptide repeats within this region altered synthesis of PrPSc.

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mentioning

confidence: 70%

Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells.

Rogers

Yehiely

Scott

et al. 1993

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

166

122

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“…A stumptail monkey inoculated at the same time died of a non-neurological illness after an observation period of 11 years; microscopic examination showed that the brain was normal. (27)(28)(29) have also experienced prolonged illnesses (5-12 years) beginning at a very early age (22)(23)(24)(25)(26)(27)(28) years).…”

Section: Resultsmentioning

confidence: 99%

Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene.

Goldfarb

Brown²,

McCombie³

et al. 1991

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

294

183

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“…1) is thought to be mostly responsible for conferring PrP with its neurotoxic and amyloidogenic properties (Selvaggini et al 1993;De Gioia et al 1994); however, the copper-binding ORs have also been implicated in misfolding. It has been clearly demonstrated that extra copies of the repeats, from one to nine additional inserts, can trigger spontaneous disease in humans (Collinge et al , 1992Owen et al 1989Owen et al , 1991Goldfarb et al 1991;Laplanche et al 1995Laplanche et al , 1999van Gool et al 1995;Campbell et al 1996;Cochran et al 1996;Windl et al 1999). In transgenic mouse experiments, OR-deletion mutants of PrP are still susceptible to disease, but the duration until disease signs appear is increased (Flechsig et al 2000).…”

Section: Introductionmentioning

confidence: 98%

Can copper binding to the prion protein generate a misfolded form of the protein?

et al. 2009

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The native prion protein (PrP) has a two domain structure, with a globular folded alpha-helical C-terminal domain and a flexible extended N-terminal region. The latter can selectively bind Cu(2+) via four His residues in the octarepeat (OR) region, as well as two sites (His96 and His111) outside this region. In the disease state, the folded C-terminal domain of PrP undergoes a conformational change, forming amorphous aggregates high in beta-sheet content. Cu(2+) bound to the ORs can be redox active and has been shown to induce cleavage within the OR region, a process requiring conserved Trp residues. Using computational modeling, we have observed that electron transfer from Trp residues to copper can be favorable. These models also reveal that an indole-based radical cation or Cu(+) can initiate reactions leading to protein backbone cleavage. We have also demonstrated, by molecular dynamics simulations, that Cu(2+) binding to the His96 and His111 residues in the remaining PrP N-terminal fragment can induce localized beta-sheet structure, allowing us to suggest a potential mechanism for the initiation of beta-sheet misfolding in the C-terminal domain by Cu(2+).

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Insertions in the prion protein gene in atypical dementias

Cited by 41 publications

References 11 publications

Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells.

Conversion of truncated and elongated prion proteins into the scrapie isoform in cultured cells.

Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene.

Can copper binding to the prion protein generate a misfolded form of the protein?

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