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Abstract
The cellular prion protein (PrPC) is subjected to various processing under physiological and pathological conditions, of which the α-cleavage within the central hydrophobic domain not only disrupts a region critical for both PrP toxicity and PrPC to PrPSc conversion but also produces the N1 fragment that is neuroprotective and the C1 fragment that enhances the pro-apoptotic effect of staurosporine in one report and inhibits prion in another. The proteases responsible for the α-cleavage of PrPC are controversial. The effect of ADAM10, ADAM17, and ADAM9 on N1 secretion clearly indicates their involvement in the α-cleavage of PrPC, but there has been no report of direct PrPC α-cleavage activity with any of the three ADAMs in a purified protein form. We demonstrated that, in muscle cells, ADAM8 is the primary protease for the α-cleavage of PrPC, but another unidentified protease(s) must also play a minor role. We also found that PrPC regulates ADAM8 expression, suggesting that a close examination on the relationships between PrPC and its processing enzymes may reveal novel roles and underlying mechanisms for PrPC in non-prion diseases such as asthma and cancer.
Disclosure of Potential Conflicts of Interest
The authors declare no conflicts of interest
