A Specific Population of Abnormal Prion Protein Aggregates Is Preferentially Taken Up by Cells and Disaggregated in a Strain-Dependent Manner

Choi, Young Pyo; Priola, Suzette A.

doi:10.1128/jvi.01484-13

Cited by 14 publications

(26 citation statements)

References 56 publications

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“…We hypothesize that strain specific differences in PrP Sc , such as sialylation, does not affect the initial targeting, which is consistent with previous work [57,58], however, the contribution of sialylation to newly formed PrP Sc in the spleen is not known [59]. We can not exclude the possibility that strain-specific requirements for cellular entry explain the failure to establish infection, however, prion uptake studies in cell culture are not consistent this hypothesis [60,61]. Detailed analysis of the early events in HY and DY TME pathogenesis failed to identify strain specific differences in transport to secondary LRS tissues.…”

Section: Discussionsupporting

confidence: 84%

PrPSc formation and clearance as determinants of prion tropism

et al. 2017

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Prion strains are characterized by strain-specific differences in neuropathology but can also differ in incubation period, clinical disease, host-range and tissue tropism. The hyper (HY) and drowsy (DY) strains of hamster-adapted transmissible mink encephalopathy (TME) differ in tissue tropism and susceptibility to infection by extraneural routes of infection. Notably, DY TME is not detected in the secondary lymphoreticular system (LRS) tissues of infected hosts regardless of the route of inoculation. We found that similar to the lymphotropic strain HY TME, DY TME crosses mucosal epithelia, enters draining lymphatic vessels in underlying laminae propriae, and is transported to LRS tissues. Since DY TME causes disease once it enters the peripheral nervous system, the restriction in DY TME pathogenesis is due to its inability to establish infection in LRS tissues, not a failure of transport. To determine if LRS tissues can support DY TME formation, we performed protein misfolding cyclic amplification using DY PrPSc as the seed and spleen homogenate as the source of PrPC. We found that the spleen environment can support DY PrPSc formation, although at lower rates compared to lymphotropic strains, suggesting that the failure of DY TME to establish infection in the spleen is not due to the absence of a strain-specific conversion cofactor. Finally, we provide evidence that DY PrPSc is more susceptible to degradation when compared to PrPSc from other lymphotrophic strains. We hypothesize that the relative rates of PrPSc formation and clearance can influence prion tropism.

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Section: Discussionsupporting

confidence: 84%

PrPSc formation and clearance as determinants of prion tropism

et al. 2017

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“…Thus, differences in infectivity cannot necessarily be attributed to different PrP Sc subpopulations separable by conventional methods such as sucrose density gradient centrifugation. Rather, the finding that biophysically more stable PrP Sc aggregates associated with a non-productive strain are more efficiently disaggregated intracellularly 83 is in line with the hypothesis that prion strains are differentially trafficked through the endolysosomal system post internalization. Identification of the subcellular compartments involved in prion strain propagation will be of considerable importance for understanding the pathogenesis associated with distinct prion strains and to unravel potential targets for prion disease intervention.…”

Section: Discussionsupporting

confidence: 69%

“…Thus, an interplay between the host cell and the physicochemical properties of prion aggregates could determine the predominant internalization pathway and access to the preferred intracellular compartments. Interestingly, immortalized brain cells have been shown to preferentially internalize PrP Sc subpopulations with comparable sedimentation properties, independent of the strain’s ability to infect cells 83 . Thus, differences in infectivity cannot necessarily be attributed to different PrP Sc subpopulations separable by conventional methods such as sucrose density gradient centrifugation.…”

Section: Discussionmentioning

confidence: 99%

Prion strains depend on different endocytic routes for productive infection

Fehlinger

Wolf

Hossinger

et al. 2017

Sci Rep

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Prions are unconventional agents composed of misfolded prion protein that cause fatal neurodegenerative diseases in mammals. Prion strains induce specific neuropathological changes in selected brain areas. The mechanism of strain-specific cell tropism is unknown. We hypothesised that prion strains rely on different endocytic routes to invade and replicate within their target cells. Using prion permissive cells, we determined how impairment of endocytosis affects productive infection by prion strains 22L and RML. We demonstrate that early and late stages of prion infection are differentially sensitive to perturbation of clathrin- and caveolin-mediated endocytosis. Manipulation of canonical endocytic pathways only slightly influenced prion uptake. However, blocking the same routes had drastic strain-specific consequences on the establishment of infection. Our data argue that prion strains use different endocytic pathways for infection and suggest that cell type-dependent differences in prion uptake could contribute to host cell tropism.

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“…Less is known about the mechanism underlying tissue tropism outside the CNS. It is possible that strain-specific replication cofactors or inhibitors govern PrP Sc formation; alternatively, strain-specific differences in the balance between PrP Sc formation and clearance may influence tissue tropism (Choi and Priola 2013).…”

Section: Prion Strain Tropismmentioning

confidence: 99%

“…These studies suggest strain-specific differences in the rate of prion replication in various tissues from natural and experimental prion disease but are limited by the complexity of the animal host and the resulting alternative explanations. For example, strain-specific differences in the rate of transport to new areas of the tissue that support prion formation, the rate of prion clearance, and differences in cell death all can contribute to the overall titer of a tissue (Ayers et al 2009;Choi and Priola 2013). In an attempt to overcome these weaknesses, the relative efficiency of PrP Sc formation was calculated using PMCA, which only measures PrP Sc formation and not clearance in a closed system (Shikiya et al 2014).…”

Section: Prion Strain Propertiesmentioning

confidence: 99%

Prion Strain Diversity

Bartz

2016

Cold Spring Harb Perspect Med

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Prion diseases affect a wide range of mammal species and are caused by a misfolded self-propagating isoform (PrP) of the normal prion protein (PrP). Distinct strains of prions exist and are operationally defined by differences in a heritable phenotype under controlled experimental transmission conditions. Prion strains can differ in incubation period, clinical signs of disease, tissue tropism, and host range. The mechanism by which a protein-only pathogen can encode strain diversity is only beginning to be understood. The prevailing hypothesis is that prion strain diversity is encoded by strain-specific conformations of PrP; however, strain-specific cellular cofactors have been identified in vitro that may also contribute to prion strain diversity. Although much progress has been made on understanding the etiological agent of prion disease, the relationship between the strain-specific properties of PrP and the resulting phenotype of disease in animals is poorly understood.

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A Specific Population of Abnormal Prion Protein Aggregates Is Preferentially Taken Up by Cells and Disaggregated in a Strain-Dependent Manner

Cited by 14 publications

References 56 publications

PrPSc formation and clearance as determinants of prion tropism

PrPSc formation and clearance as determinants of prion tropism

Prion strains depend on different endocytic routes for productive infection

Prion Strain Diversity

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