The cellular prion protein (PrP(C) ) plays important roles in neurodegenerative diseases. First of all, it is the well-established substrate for the conformational conversion into its pathogenic isoform (PrP(S) (c) ) giving rise to progressive and fatal prion diseases. Moreover, several recent reports highlight important roles of PrP(C) in other neurodegenerative conditions such as Alzheimer's disease. Since PrP(C) is subject to proteolytic processing, here, we discuss the two main cleavage events under physiological conditions, the α-cleavage and the shedding. We will focus on how these cleavages and the resulting fragments may impact prion diseases as well as other neurodegenerative proteinopathies. Finally, we will discuss the recently identified sheddase of PrP(C) , namely the metalloprotease ADAM10, with regard to therapeutic potential against neurodegenerative diseases. © 2013 The Authors Journal compilation © 2013 FEBS.