Description:
<jats:p>The cellular prion protein (Pr<jats:styled-content style="fixed-case">P<jats:sup>C</jats:sup></jats:styled-content>) plays important roles in neurodegenerative diseases. First, it is the well‐established substrate for the conformational conversion into its pathogenic isoform (Pr<jats:styled-content style="fixed-case">P<jats:sup>S</jats:sup></jats:styled-content><jats:sup>c</jats:sup>) giving rise to progressive and fatal prion diseases. Moreover, several recent reports highlight important roles of Pr<jats:styled-content style="fixed-case">P<jats:sup>C</jats:sup></jats:styled-content> in other neurodegenerative conditions such as Alzheimer's disease. Since Pr<jats:styled-content style="fixed-case">P<jats:sup>C</jats:sup></jats:styled-content> is subject to proteolytic processing, here we discuss the two main cleavage events under physiological conditions, α‐cleavage and shedding. We focus on how these cleavages and the resulting fragments may impact prion diseases as well as other neurodegenerative proteinopathies. Finally, we discuss the recently identified sheddase of Pr<jats:styled-content style="fixed-case">P<jats:sup>C</jats:sup></jats:styled-content>, namely the metalloprotease <jats:styled-content style="fixed-case">ADAM</jats:styled-content>10, with regard to therapeutic potential against neurodegenerative diseases.</jats:p>