Lack of a-disintegrin-and-metalloproteinase ADAM10 leads to intracellular accumulation and loss of shedding of the cellular prion protein in vivo

BACKGROUND: 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. RESULTS: 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). CONCLUSION: 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.