The precursor form of the nerve growth factor (proNGF) like its mature form is characterized by the cystin knot motif consisting of three cystine bridges, whereas proneurotrophins and mature neurotrophins elicit opposite biological effects. ProNGF functions preferentially via the complex of pan-neurotrophin receptor p75 (p75NTR) and vps10p domain-containing receptor sortilin inducing neuronal apoptosis and contributing to age- and disease-related neurodegeneration.