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

Autor: Kraemer BR; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States. Electronic address: bradley.kraemer@eku.edu., Clements RT; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States., Escobedo CM; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States., Nelson KS; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States., Waugh CD; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States., Elliott AS; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States., Hall WC; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States., Schemanski MT; From the Department of Biological Sciences, Eastern Kentucky University, Richmond, KY 40475, United States.
Jazyk: angličtina
Zdroj: Neuroscience [Neuroscience] 2021 Jan 15; Vol. 453, pp. 222-236. Date of Electronic Publication: 2020 Nov 28.
DOI: 10.1016/j.neuroscience.2020.11.036
Abstrakt: 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.
(Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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