The cellular prion protein (PrP^C) fulfils several yet not completely understood physiological functions. Apart from these functions, it has the ability to misfold into a pathogenic scrapie form (PrP^Sc) leading to fatal transmissible spongiform encephalopathies. Proteolytic processing of PrP^C generates N- and C-terminal fragments which play crucial roles both in the pathophysiology of prion diseases and in transducing physiological functions of PrP^C. A-disintegrin-and-metalloproteinase 10 (ADAM10) has been proposed by cell culture experiments to be responsible for both shedding of PrP^C and its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrP^C in vivo.

Using neuron-specific Adam10 knockout mice, we show that ADAM10 is the sheddase of PrP^C and that its absence in vivo leads to increased amounts and accumulation of PrP^C in the early secretory pathway by affecting its posttranslational processing. Elevated PrP^C levels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrP^C.

Our study elucidates the proteolytic processing of PrP^C and proves a role of ADAM10 in shedding of PrP^C in vivo. We suggest that ADAM10 is a mediator of PrP^C homeostasis at the plasma membrane and, thus, might be a regulator of the multiple functions discussed for PrP^C. Furthermore, identification of ADAM10 as the sheddase of PrP^C opens the avenue to devising novel approaches for therapeutic interventions against prion diseases.