The p75 neurotrophin receptor (p75NTR) is a transmembrane protein receptor with multiple functions including regulating cell survival, neurite outgrowth, and myelination of many distinct populations of neurons. While its signaling mechanisms are still somewhat poorly understood, it is known that binding of neurotrophins to p75NTR’s extracellular domain results in cleavage of the receptor occurs through TACE and y-secretase activity. Of the conditions in which p75NTR is activated, many are associated with oxidative stress. In recent studies, inducing oxidative stress in sympathetic neurons has been shown to promote the proteolysis of p75NTR leading to neurite degeneration and the death, but whether oxidative stress induces cleavage of p75NTR in all types of neurons is still unknown. Oxidative stress is associated with a variety of neuropathological conditions, so we hypothesized that p75NTR could be activated this way in other neuronal populations susceptible to these pathologies. Dopaminergic neurons are particularly susceptible to oxidative stress, as they are the population of neurons which degenerate during the progression of Parkinson’s disease. Dopaminergic neurons are known to express p75NTR, but the mechanisms by which p75NTR signals in this population are currently unknown. Here we investigate whether oxidative stress stimulates p75NTR signaling in dopaminergic neurons. Our findings indicate that following exposure to ROS, proteolysis of p75NTR in dopaminergic cells occurs. Furthermore, activation of c-Jun N-terminal kinase (JNK) is necessary for the proteolysis of p75NTR to occur through metalloprotease and y-secretase activity. Preliminary data indicates that p75NTR has a pro-survival role in dopaminergic neurons following exposure to oxidative stress.
Semester/Year of Award
Bradley R. Kraemer
Restricted Access Thesis
Clements, Rachel T., "Investigating the Proteolysis of p75NTR in Response to Oxidative Stress in Dopaminergic Neurons" (2019). Honors Theses. 679.