Cellular Prion Protein Regulates Its Own α-Cleavage through ADAM8 in Skeletal Muscle

The ubiquitously expressed cellular prion protein (PrPC) is subjected to the physiological alpha-cleavage at a region critical for both PrP toxicity and the conversion of PrPC to its pathogenic prion form (PrPSc), generating the C1 and N1 fragments. The C1 fragment can activate caspase 3 while the N1 fragment is neuroprotective. Recent articles indicate that ADAM10, ADAM17, and ADAM9 may not play a prominent role in the alpha-cleavage of PrPC as previously thought, raising questions on the identity of the responsible protease(s). Here we show that, ADAM8 can directly cleave PrP to generate C1 in vitro and PrP C1/full-length ratio is greatly decreased in the skeletal muscles of ADAM8 knock-out mice; in addition, the PrP C1/full-length ratio is linearly correlated with ADAM8 protein level in myoblast cell line C2C12 and in skeletal muscle tissues of transgenic mice. These results indicate that ADAM8 is the primary protease responsible for the alpha-cleavage of PrPC in muscle cells. Moreover, we found that overexpression of PrPC led to up-regulation of ADAM8, suggesting that PrPC may regulate its own alpha-cleavage through modulating ADAM8 activity.