Regulation of proneurotrophin-induced neuronal death and plasticity: Mechanisms of receptor activation and signaling

Neurotrophins are initially translated as precursors, or proneurotrophins, which can be locally processed to a C-terminal mature form. Mature neurotrophins activate Trk receptor tyrosine kinases to promote survival, differentiation, and long term potentiation (LTP) with well defined mechanisms, whereas proneurotrophins utilize a dual receptor system of p75NTR and sortilin to initiate apoptosis or long term depression (LTD). To better understand proneurotrophin actions in the mammalian nervous system, potential mechanisms that regulate neuronal susceptibility to proneurotrophins were investigated. Although p75NTR is highly expressed on the plasma membrane and accessible to proneurotrophin ligands, sortilin is primarily localized to the Golgi, endosomes or lysosomes, limiting the formation of a cell surface co-receptor complex. In this study, we found that a mammalian homolog of p75NTR, named NRH2, specifically re-targets sortilin, from a lysosomal fate to the cell surface to promote the formation of a dual receptor complex of p75NTR and sortilin, and render neurons sensitive to apoptosic actions of proneurotrophins. We also identified that SorCS2, a member in the sortilin family, can also bind proBDNF, but confer a number of distinct features as compared to sortilin. In CNS neurons, SorCS2 highly localizes to the dendritic processes, and undergoes constitutive ectodomain shedding, while sortilin expression in the distal dendrites is negligible, and ectodomain cleavage is rapidly occurred upon neuronal activation, suggesting that sortilin and SorCS2 may play a distinct role as proBDNF chaperone and receptor. To further investigate the mechanisms of proneurophin-inducible signaling, we screened novel p75NTR interactors in reconstitutive cell systems, and found the RIP kinases, Trio and ATF6 as potential mediators to initiate proneurotrophin signaling pathways.