c-Jun N-terminal Kinase Mediates Ligand-independent p75 NTR Signaling in Mesencephalic Cells Subjected to Oxidative Stress

The p75 neurotrophin receptor (p75 ) is a multifunctional protein that regulates cellular responses to pathological conditions in specific regions of the nervous system. Activation of p75 in certain neuronal populations induces proteolytic processing of the receptor, thereby generating p75 fragments that facilitate downstream signaling. Expression of p75 has been reported in neurons of the ventral midbrain, but p75 signaling mechanisms in such cells are poorly understood. Here, we used Lund Human Mesencephalic cells, a population of neuronal cells derived from the ventral mesencephalon, to evaluate the effects of oxidative stress on p75 signaling. Subjection of the cells to oxidative stress resulted in decreased cell-surface localization of p75 and intracellular accumulation of p75 fragments. Oxidative stress-induced p75 processing was reduced by pharmacological inhibition of metalloproteases or γ-secretase, but was unaltered by blockade of the ligand-binding domain of p75 . Furthermore, inhibition of c-Jun N-terminal Kinase (JNK) decreased p75 cleavage induced by oxidative damage. Altogether, these results support a mechanism of p75 activation in which oxidative stress stimulates JNK signaling, thereby facilitating p75 processing via a ligand-independent mechanism involving induction of metalloprotease and γ-secretase activity. These findings reveal a novel role for JNK in ligand-independent p75 signaling, and, considering the susceptibility of mesencephalic neurons to oxidative damage associated with Parkinson's disease (PD), merit further investigation into the effects of p75 on PD-related neurodegeneration.