Prion strain discrimination using luminescent conjugated polymers

Sigurdson, Christina J.; Nilsson, K. Peter R.; Hornemann, Simone; Manco, Giuseppe; Polymenidou, Magdalini; Schwarz, Petra; Leclerc, Mario; Hammarström, Per; Wüthrich, Kurt; Aguzzi, Adriano

doi:10.1038/nmeth1131

Cited by 259 publications

(289 citation statements)

References 30 publications

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“…However, by the third (n ϭ 3/4) and fourth (n ϭ 5/5) passage derived from mouse ''a'' (Fig. 2 A), RL 3 tga20 brain homogenates displayed abundant PK-resistant PrP [27][28][29][30] (Fig. 3A).…”

Section: Rl-prp Prion Strain Propertiesmentioning

confidence: 99%

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De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

Sigurdson¹,

Nilsson²,

Hornemann

et al. 2009

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

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Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations that subtly affect the structure of its globular domain, causes a fully penetrant lethal spongiform encephalopathy with cerebral PrP plaques. This genetic disease was reproduced with 100% attack rate by intracerebral inoculation of brain homogenate to tga20 mice overexpressing WT PrP, and from the latter to WT mice, but not to PrP-deficient mice. Upon successive transmissions, the incubation periods decreased and PrP became more protease-resistant, indicating the presence of a strain barrier that was gradually overcome by repeated passaging. This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease.amyloid ͉ neurodegeneration ͉ prion ͉ species barrier ͉ transgenic mice

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Section: Rl-prp Prion Strain Propertiesmentioning

confidence: 99%

“…Prion strains often differ in the affinity of PrP deposits for amyloidotropic dyes (29). This property can differentiate strains even when propagated in congenic hosts.…”

Section: Differential Staining Of Rl-prp With Luminescent Conjugated mentioning

confidence: 99%

De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

Sigurdson¹,

Nilsson²,

Hornemann

et al. 2009

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

Self Cite

178

198

View full text Add to dashboard Cite

show abstract

“…Very recently, luminescent conjugated polymers (polythiophene acetic acid polythiophene methyl imidazole), which exhibit conformation-dependant emission spectra on TSE-infected brain sections, have been able to detect changes in PrP Sc conformations that were invisible by Western blot, during serial adaptation of CWD to mouse transgenic for mouse PrP [180]. Spectral changes were noted over four passages of CWD, suggesting a gradual, host-constrained change in the supramolecular arrangement of PrP Sc deposits within the brain.…”

Section: Molecular Conformation Of Prp Sc During Cross-species Transmmentioning

confidence: 99%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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“…However, elk CWD and human sCJD MM1 strains exhibited distinct glycoform patterns by two dimensional gel electrophoresis, suggesting that the strains differed. Future studies may incorporate use of luminescent conjugated polymers, which were recently shown to distinguish naturally-and experimentally-derived prion strains [79].…”

Section: Human Susceptibility To Cwdmentioning

confidence: 99%

A prion disease of cervids: Chronic wasting disease

2008

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-Chronic wasting disease (CWD) is a prion disease of deer, elk, and moose, initially recognized in Colorado mule deer. The discovery of CWD beyond the borders of Colorado and Wyoming, in Canada and as far east as New York, has led to its emergence as a prion disease of international importance. Epidemiological studies indicate that CWD is horizontally transmitted among free-ranging animals, potentially indirectly by prion-containing secreta or excreta contaminating the environment. Experimental CWD transmission attempts to other wild and domestic mammals and to transgenic mice expressing the prion protein of cattle, sheep, and humans have shed light on CWD species barriers. Transgenic mice expressing the cervid prion protein have proven useful for assessing the genetic influences of Prnp polymorphisms on CWD susceptibility. Accumulating evidence of CWD pathogenesis indicates that the misfolded prion protein or prion infectivity seems to be widely disseminated in many nonneural organs and in blood. This review highlights contemporary research findings in this prion disease of free-ranging wildlife.

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Prion strain discrimination using luminescent conjugated polymers

Cited by 259 publications

References 30 publications

De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

Prion agent diversity and species barrier

A prion disease of cervids: Chronic wasting disease

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