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The story of prions gets increasingly bizarre. The peculiar pathogenicity of prion protein (PrP) makes understanding and treating the resulting diseases difficult. Now, on page 703, Peters et al. provide evidence that PrP also uses an unusual endocytic pathway en route to lysosomes.The harmless version of PrP is processed and directed to caveolin-rich glycolipid rafts at the plasma membrane, although its function remains a mystery. The misfolded pathogenic form, however, is found in late endosomes and lysosomes. The group now shows that, unlike most internalized proteins, which use the typical clathrin-dependent endocytosis pathway, PrP finds its way to lysosomes through an endosomal compartment that lacks clathrin but contains caveolin-1.
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The results contrast another study that reported colocalization of PrP and clathrin in vesicles. But the cryoimmunogold EM method used by Peters et al. allows for higher resolution of the vesicles and their contents. Simian virus 40 particles were also shown to be taken in through caveolin-containing, clathrin-negative structures that are connected to an endocytic vacuole (collectively termed caveosomes). Although the PrP-containing vesicles lacked virus, the two atypical endocytic structures may be one and the same. If so, this EM study is the first ultrastructural view of caveosomes, which contain raft domains that are preferred by membrane-bound PrP.
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Both the low pH and high concentration of raft lipids in the caveolin-containing compartment may favor PrP conversion to the pathogenic form. Therefore, the group expects that caveolin knock-out mice should be less susceptible to oral prions, but they await use of these mice to test their theory. In the meantime, they are testing whether drugs such as statins, which interfere with cholesterol-rich raft domains, might slow prion disease progression.(PrP (small gold particles) is found in e) |
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发表于 2009-3-6 00:48
发表于 2024-5-8 17:05
