Abstract: The cellular prion protein (PrPC) is a truly remarkable cell surface glycoprotein. With (i) its broad expression pattern and (ii) particularly high levels in the nervous system, (iii) its critical involvement in fatal neurodegenerative diseases affecting different mammalian species, (iv) its structurally diverging bipartite buildup, (v) its high degree of evolutionary conservation and (vi) a variety of –at least suggested– functions despite (vii) a surprising lack of major phenotypic deficits when absent (as in respective knock-out animals), PrPC has raised considerable research interest over the last four decades. While most of these aspects have been reviewed extensively in the past (Linsenmeier et al., 2017), this perspective will focus exclusively on a soluble peptide, termed N1, which is constitutively generated by the main proteolytic cleavage event occurring on PrPC (Figure 1B). In fact, considering that particular fragments of PrPC account for intrinsic functions, may help to explain the multitude of physiological roles so far mostly –and maybe in part mistakenly– attributed to full-length PrPC as the ‘precursor’. The N1 fragment basically consists of the flexible N-terminal half of PrPC (after removal of the signal peptide) ranging from residue 23 to ~110, contains several sites for coordinative binding of divalent cations and interaction with other binding partners, and represents a prime example of an intrinsically disordered peptide (Gonsberg et al., 2017). Physiologically it results from the α-cleavage of PrPC which may take place at or en route to the cell surface or after re-internalization in endosomal compartments. It is eventually released into the extracellular space and tissue/body fluids where it is expected to exert its functions. Of note, while candidates have been suggested and controversially discussed, the responsible protease has not been convincingly identified yet, thus precluding any pharmacological manipulation at present. It would not even be surprising if different proteases could orchestrate and ensure this important cleavage in a redundant fashion (Linsenmeier et al., 2017).