title: A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress.
abstract: The p75 neurotrophin receptor (p75(NTR)) mediates the death of specific populations of neurons during the development of the nervous system or after cellular injury. The receptor has also been implicated as a contributor to neurodegeneration caused by numerous pathological conditions. Because many of these conditions are associated with increases in reactive oxygen species, we investigated whether p75(NTR) has a role in neurodegeneration in response to oxidative stress. Here we demonstrate that p75(NTR) signaling is activated by 4-hydroxynonenal (HNE), a lipid peroxidation product generated naturally during oxidative stress. Exposure of sympathetic neurons to HNE resulted in neurite degeneration and apoptosis. However, these effects were reduced markedly in neurons from p75(NTR-/-) mice. The neurodegenerative effects of HNE were not associated with production of neurotrophins and were unaffected by pretreatment with a receptor-blocking antibody, suggesting that oxidative stress activates p75(NTR) via a ligand-independent mechanism. Previous studies have established that proteolysis of p75(NTR) by the metalloprotease TNFα-converting enzyme and γ-secretase is necessary for p75(NTR)-mediated apoptotic signaling. Exposure of sympathetic neurons to HNE resulted in metalloprotease- and γ-secretase-dependent cleavage of p75(NTR). Pharmacological blockade of p75(NTR) proteolysis protected sympathetic neurons from HNE-induced neurite degeneration and apoptosis, suggesting that cleavage of p75(NTR) is necessary for oxidant-induced neurodegeneration. In vivo, p75(NTR-/-) mice exhibited resistance to axonal degeneration associated with oxidative injury following administration of the neurotoxin 6-hydroxydopamine. Together, these data suggest a novel mechanism linking oxidative stress to ligand-independent cleavage of p75(NTR), resulting in axonal fragmentation and neuronal death.
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Kraemer
authors.affiliation: From the Departments of Biochemistry.
authors.forename: John P
authors.initials: JP
authors.lastname: Snow
authors.affiliation: Psychiatry, Pharmacology.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollbrecht
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Amrita
authors.initials: A
authors.lastname: Pathak
authors.affiliation: Pathology, Microbiology, and Immunology, the Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: William M
authors.initials: WM
authors.lastname: Valentine
authors.affiliation: Psychiatry, Pharmacology.
authors.forename: Ariel Y
authors.initials: AY
authors.lastname: Deutch
authors.affiliation: From the Departments of Biochemistry, bruce.carter@vanderbilt.edu.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Carter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001369:Axons; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D058609:Visual Field Tests
chemical_list: D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C068313:Ngfr protein, rat
keywords: Apoptosis; Axonal Degeneration; Neurodegeneration; Neurotrophin; Oxidative Stress; Reactive Oxygen Species (ROS); p75 Neurotrophin Receptor