Oxidative Stress Induces p75NTR Signaling in Midbrain Dopaminergic Cells

The p75 Neurotrophin Receptor (p75NTR) is a transmembrane protein with an established role in regulating the survival of neurons that have been impacted by an injury or neurological disorder. Injury to nervous tissue can result in cellular production and secretion of neurotrophins, ligands that activate p75NTR and stimulate pro-apoptotic signaling. During this process, activation of p75NTR by neurotrophins leads to cleavage of p75NTR by the metalloprotease ADAM17 and the γ-secretase complex. Cleavage of p75NTR in this manner releases fragments of p75NTR to interact with a variety of cytosolic signaling proteins, ultimately leading to neuronal death. We previously discovered that cleavage of p75NTR is induced in sympathetic neurons subjected to oxidative stress, a cellular condition that is commonly associated with a variety of neurological conditions. Surprisingly, activation of p75NTR in this context did not require neurotrophins. This novel, neurotrophin-independent mechanism of p75NTR activation may underlie the ability of the receptor to promote neurodegeneration induced by a variety of pathological conditions; however, whether oxidative stress activates p75NTR signaling in neurons of the brain has not been explored. Here, we demonstrate that p75NTR is expressed in midbrain dopaminergic neurons, a cell population that is vulnerable to oxidative stress and progressive neurodegeneration in individuals with Parkinson’s disease. Subjection of dopaminergic cells to oxidative stress resulted in cleavage of p75NTR by ADAM17 and γ‑secretase. Our preliminary data indicate that oxidative stress-induced proteolysis of p75NTR occurs via a neurotrophin-independent mechanism. These studies reveal a novel mechanism through which p75NTR may regulate neurodegeneration associated with Parkinson’s disease