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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.

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