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

<p>Abstract</p> <p>Background</p> <p>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^Cgenerates 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^Cand its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrP^C<it>in vivo</it>.</p> <p>Results</p> <p>Using neuron-specific <it>Adam10 </it>knockout mice, we show that ADAM10 is the sheddase of PrP^Cand that its absence <it>in vivo </it>leads to increased amounts and accumulation of PrP^Cin the early secretory pathway by affecting its posttranslational processing. Elevated PrP^Clevels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrP^C.</p> <p>Conclusion</p> <p>Our study elucidates the proteolytic processing of PrP^Cand proves a role of ADAM10 in shedding of PrP^C<it>in vivo</it>. We suggest that ADAM10 is a mediator of PrP^Chomeostasis 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^Copens the avenue to devising novel approaches for therapeutic interventions against prion diseases.</p