title: Cellular prion protein regulates its own α-cleavage through ADAM8 in skeletal muscle.
abstract: The ubiquitously expressed cellular prion protein (PrP(C)) is subjected to the physiological α-cleavage at a region critical for both PrP toxicity and the conversion of PrP(C) to its pathogenic prion form (PrP(Sc)), 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 α-cleavage of PrP(C) 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 α-cleavage of PrP(C) in muscle cells. Moreover, we found that overexpression of PrP(C) led to up-regulation of ADAM8, suggesting that PrP(C) may regulate its own α-cleavage through modulating ADAM8 activity.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Debra
authors.initials: D
authors.lastname: Sorensen
authors.forename: Sarah
authors.initials: S
authors.lastname: Medina
authors.forename: Sergei
authors.initials: S
authors.lastname: Ilchenko
authors.forename: Janna
authors.initials: J
authors.lastname: Kiselar
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Booth
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D015703:Antigens, CD; D008565:Membrane Proteins; D018621:PrPC Proteins; D051722:ADAM Proteins; C489402:Adam8 protein, mouse