PrPC homodimerization stimulates the production of PrPC cleaved fragments PrPN1 and PrPC1

Abstract

An endoproteolytic cleavage termed α-cleavage between residues 111/112 is a characteristic feature of the cellular prion protein (PrP C). This cleavage generates a soluble N-terminal fragment (PrPN1) and a glycosylphosphatidylinositol-anchored C-terminal fragment (PrPC1). Independent studies demonstrate that modulating PrP C α-cleavage represents a potential therapeutic strategy in prion diseases. The regulation of PrP C α-cleavage is unclear. The only known domain that is essential for the α-cleavage to occur is a hydrophobic domain (HD). Importantly, the HD is also essential for the formation of PrP C homodimers. To explore the role of PrP C homodimerization on the α-cleavage, we used a well described inducible dimerization strategy whereby a chimeric PrP C composed of a modified FK506- binding protein (Fv) fused with PrP C and termed Fv-PrP is incubated in the presence of a dimerizer AP20187 ligand. We show that homodimerization leads to a considerable increase of PrP C α-cleavage in cultured cells and release of PrPN1 and PrPC1. Interestingly, enforced homodimerization increased PrP C levels at the plasma membrane, and preventing PrP C trafficking to the cell surface inhibited dimerization-induced α-cleavage. These observations were confirmed in primary hippocampal neurons from transgenic mice expressing Fv-PrP. The proteases responsible for the α-cleavage are still elusive, and in contrast to initial studies we confirm more recent investigations that neither ADAM10 nor ADAM17 are involved. Importantly, PrPN1 produced after PrP C homodimerization protects against toxic amyloid-β (Aβ) oligomers. Thus, our results show that PrP C homodimerization is an important regulator of PrP C α-cleavage and may represent a potential therapeutic avenue against Aβ toxicity in Alzheimer's disease. © 2012 the authors.