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• W4313251449 abstract "The cellular prion protein (PrPC) converts to alternatively folded pathogenic conformations (PrPSc) in prion infections and binds neurotoxic oligomers formed by amyloid-β α-synuclein, and tau. β-Endoproteolysis, which splits PrPC into N- and C-terminal fragments (N2 and C2, respectively), is of interest because a protease-resistant, C2-sized fragment (C2Sc) accumulates in the brain during prion infections, seemingly comprising the majority of PrPSc at disease endpoint in mice. However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in vivo. Here, a cell-based screen of protease inhibitors unexpectedly linked type II membrane proteins of the S9B serine peptidase subfamily to PrPC β-cleavage. Overexpression experiments in cells and assays with recombinant proteins confirmed that fibroblast activation protein (FAP) and its paralog, dipeptidyl peptidase-4 (DPP4), cleave directly at multiple sites within PrPC's N-terminal domain. For wild-type mouse and human PrPC substrates expressed in cells, the rank orders of activity were human FAP ~ mouse FAP > mouse DPP4 > human DPP4 and human FAP > mouse FAP > mouse DPP4 >> human DPP4, respectively. C2 levels relative to total PrPC were reduced in several tissues from FAP-null mice, and, while knockout of DPP4 lacked an analogous effect, the combined DPP4/FAP inhibitor linagliptin, but not the FAP-specific inhibitor SP-13786, reduced C2Sc and total PrPSc levels in two murine cell-based models of prion infections. Thus, the net activity of the S9B peptidases FAP and DPP4 and their cognate inhibitors/modulators affect the physiology and pathogenic potential of PrPC." @default.
• W4313251449 created "2023-01-06" @default.
• W4313251449 creator A5000109345 @default.
• W4313251449 creator A5014473479 @default.
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• W4313251449 creator A5065206201 @default.
• W4313251449 creator A5085801377 @default.
• W4313251449 date "2022-12-27" @default.
• W4313251449 modified "2023-09-25" @default.
• W4313251449 title "Beta-endoproteolysis of the cellular prion protein by dipeptidyl peptidase-4 and fibroblast activation protein" @default.
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• W4313251449 doi "https://doi.org/10.1073/pnas.2209815120" @default.
• W4313251449 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36574660" @default.
• W4313251449 hasPublicationYear "2022" @default.
• W4313251449 type Work @default.
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• W4313251449 hasAuthorship W4313251449A5000109345 @default.
• W4313251449 hasAuthorship W4313251449A5014473479 @default.
• W4313251449 hasAuthorship W4313251449A5024168823 @default.
• W4313251449 hasAuthorship W4313251449A5038926400 @default.

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