Influence of ADAM10 on prion protein processing and scrapie infectiosity in vivo.
Both the cellular prion protein (PrP(c)) and the amyloid precursor protein (APP) are physiologically subjected to complex proteolytic processing events. While for APP the proteinases involved--alpha-, beta- and gamma-secretase--have been identified in vitro and in vivo, the cleavage of PrP(c) by now has been linked only to the shedding activity of the metalloproteinase ADAM10 and/or ADAM17 in cell culture. Here we show that neuronal overexpression of the alpha-secretase ADAM10 in mice reduces all PrP(c) species detected in the brain instead of leading to enhanced amounts of specific cleavage products of PrP(c). Additionally, the incubation time of mice after scrapie infection is significantly increased in mice moderately overexpressing ADAM10. This indicates that overexpression of ADAM10 rather influences the amount of the cellular prion protein than its processing in vivo.
Endres
Kristina
K
Institute of Biochemistry, Johannes Gutenberg-University, Johann-Joachim-Becherweg 30, D-55128 Mainz, Germany. endres@uni-mainz.de
Mitteregger
Gerda
G
Kojro
Elzbieta
E
Kretzschmar
Hans
H
Fahrenholz
Falk
F
D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072197:ADAM10 Protein; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D002417:Cattle; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011328:Prions / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012608:Scrapie / Q000201:enzymology* / Q000517:prevention & control / Q000635:transmission*
D008565:Membrane Proteins; D011328:Prions; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human