Peptide aptamer-mediated modulation of prion protein α-cleavage as treatment strategy for prion and other neurodegenerative diseases

[...]PrP100–120 harbors one high affinity binding site for toxic amyloid β-oligomers (Aβo) which are associated with pathogenesis of AD. [...]proteolytic processing of the cellular prion protein is not totally understood. [...]three main proteolytic cleavage events have been described: physiological α-cleavage at amino acids 110–111/112 [Figure 1], β-cleavage at amino acids 89/90 executed by calpains upon oxidative stress, and shedding at amino acids 228/229 mainly by the zinc metalloproteinase ADAM10 (Béland and Roucou, 2014). Notably, it cannot be converted to PrPSc and moreover, acts as a dominant-negative inhibitor of PrPSc formation. [...]enhancing α-cleavage represents a valuable treatment target for prion diseases and possibly other neurodegenerative diseases that benefit from high levels of neuroprotective PrPN1 and/or proteolysis of PrPC at the hydrophobic domain (Béland and Roucou, 2014). [...]high levels of PrPC1 act as a negative inhibitor for prion conversion.