1887

Abstract

Transmissible spongiform encephalopathies are characterized by the accumulation of PrP, a protease-resistant form of a host-derived protein termed PrP. Substantial evidence indicates that PrP represents an essential component of the infectious agent, which is termed prion. The accumulation of PrP within the central nervous system of prion-infected organisms is a dynamic process that is regulated both by production and by clearance of PrP. Although several proteases have been implicated in proteolysis of PrP, the mechanisms underlying proteolysis of PrP remain unclear. Here, it was investigated whether neprilysin, a metalloprotease known to degrade extracellular amyloidogenic proteins such as amyloid-, plays a role in prion pathogenesis . As neprilysin has a broad substrate specificity and is localized subcellularly in the vicinity of PrP, it represents a plausible candidate for prion degradation. Prions were therefore administered to mice lacking or overexpressing neprilysin in brain. However, the gene dosage of neprilysin did not modulate accumulation of PrP in brain. Also, incubation times and clinical course of prion disease, as well as brain infectivity titres at terminal stage, were unaffected. These data rule out neprilysin as a major modulator of PrP accumulation and prion pathogenesis.

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2005-06-01
2019-10-17
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