While α-cleavage, occurring in the middle of the PrPC sequence and producing a soluble N1 and a membrane-attached C1 fragment, confers neuroprotection with regard to prion diseases (Lewis et al., 2009; Westergard et al., 2011; Turnbaugh et al., 2012; Campbell et al., 2013) and Aβ-associated neurotoxicity (Guillot-Sestier et al., 2009; Resenberger et al., 2011; Beland et al., 2012; Guillot-Sestier et al., 2012; Fluharty et al., 2013), the role of an extreme C-terminal cleavage in close proximity to the plasma membrane, termed shedding, remains enigmatic. The gene discussed is PRNP; the disease is prion disease.