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

ABSTRACT: The p75 neurotrophin receptor (p75^NTR) is a multifunctional protein that regulates cellular responses to pathological conditions in specific regions of the nervous system. Activation of p75^NTR in certain neuronal populations induces proteolytic processing of the receptor, thereby generating p75^NTR fragments that facilitate downstream signaling. Expression of p75^NTR has been reported in neurons of the ventral midbrain, but p75^NTR 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^NTR signaling. Subjection of the cells to oxidative stress resulted in decreased cell-surface localization of p75^NTR and intracellular accumulation of p75^NTR fragments. Oxidative stress-induced p75^NTR processing was reduced by pharmacological inhibition of metalloproteases or γ-secretase, but was unaltered by blockade of the ligand-binding domain of p75^NTR. Furthermore, inhibition of c-Jun N-terminal Kinase (JNK) decreased p75^NTR cleavage induced by oxidative damage. Altogether, these results support a mechanism of p75^NTR activation in which oxidative stress stimulates JNK signaling, thereby facilitating p75^NTR 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^NTR 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^NTR on PD-related neurodegeneration.

SUBMITTER: Kraemer BR 

PROVIDER: S-EPMC8783671 | biostudies-literature |

REPOSITORIES: biostudies-literature