What is it about?
In the fatal brain disorders known as prion diseases, the cellular prion protein (PrPC) is converted into an abnormal structure by infectious, misfolded prion protein molecules. PrPC can also interact with other types of misfolded protein found in other neurodegenerative brain diseases. But, depending on how the PrPC molecules are fragmented, interactions with disease-promoting misfolded proteins are either allowed or blocked.
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Why is it important?
We have used a high throughput screen of protease inhibitors, as well as cell-free systems, to obtain a better understanding of PrPC fragmentation processes. We demonstrate disease-promoting β-cleavage of PrPC by two related, cell-surface proteases, namely dipeptidyl peptidase-4, DPP4, and fibroblast activation protein, FAP. By applying inhibitors of these serine proteases to prion-infected cells, we also show that the β-cleavage activity of dipeptidyl peptidase-4 in particular may be important in the pathogenesis of prion diseases.
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This page is a summary of: Beta-endoproteolysis of the cellular prion protein by dipeptidyl peptidase-4 and fibroblast activation protein, Proceedings of the National Academy of Sciences, December 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2209815120.
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