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In Vitro and In Vivo Evidence towards Fibronectin’s Protective Effects against Prion Infection
oleh: M. Carmen Garza, Sang-Gyun Kang, Chiye Kim, Eva Monleón, Jacques van der Merwe, David A. Kramer, Richard Fahlman, Valerie L. Sim, Judd Aiken, Debbie McKenzie, Leonardo M. Cortez, Holger Wille
Format: | Article |
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Diterbitkan: | MDPI AG 2023-12-01 |
Deskripsi
A distinctive signature of the prion diseases is the accumulation of the pathogenic isoform of the prion protein, PrP<sup>Sc</sup>, in the central nervous system of prion-affected humans and animals. PrP<sup>Sc</sup> is also found in peripheral tissues, raising concerns about the potential transmission of pathogenic prions through human food supplies and posing a significant risk to public health. Although muscle tissues are considered to contain levels of low prion infectivity, it has been shown that myotubes in culture efficiently propagate PrP<sup>Sc</sup>. Given the high consumption of muscle tissue, it is important to understand what factors could influence the establishment of a prion infection in muscle tissue. Here we used in vitro myotube cultures, differentiated from the C2C12 myoblast cell line (dC2C12), to identify factors affecting prion replication. A range of experimental conditions revealed that PrP<sup>Sc</sup> is tightly associated with proteins found in the systemic extracellular matrix, mostly fibronectin (FN). The interaction of PrP<sup>Sc</sup> with FN decreased prion infectivity, as determined by standard scrapie cell assay. Interestingly, the prion-resistant reserve cells in dC2C12 cultures displayed a FN-rich extracellular matrix while the prion-susceptible myotubes expressed FN at a low level. In agreement with the in vitro results, immunohistopathological analyses of tissues from sheep infected with natural scrapie demonstrated a prion susceptibility phenotype linked to an extracellular matrix with undetectable levels of FN. Conversely, PrP<sup>Sc</sup> deposits were not observed in tissues expressing FN. These data indicate that extracellular FN may act as a natural barrier against prion replication and that the extracellular matrix composition may be a crucial feature determining prion tropism in different tissues.