title: Tumor necrosis factor-alpha receptor 1 (p55) knockout only transiently decreases the activation of c-Jun and does not affect the survival of axotomized dopaminergic nigral neurons.
abstract: The activation of the c-Jun N-terminal kinases and their substrate transcription factor c-Jun is central to the death of dopaminergic neurons of the substantia nigra pars compacta (SNC) but the underlying signal cascades are poorly understood. We have studied the impact of the p55 tumor necrosis factor-alpha receptor (TNF-R) 1 on the N-terminal phosphorylation of c-Jun and the survival of the dopaminergic SNC neurons after transection of the medial forebrain bundle. The axotomy raised the immunoreactivities of tumor necrosis factor-alpha, p75 TNF-R2 and ED1 (ectodysplasin A) in the substantia nigra equally in wildtype and knockout (ko) mice and of TNF-R1 in wildtype mice. Importantly, TNF-R1 ko significantly reduced the early phosphorylation of c-Jun between 18 h and 3 d post-axotomy but the functional deficiency of TNF-R1 did not affect the survival of the dopaminergic neurons up to day 30. These findings demonstrate that: (i) TNF-R1 is involved in the early cell body response after axon transection; (ii) TNF-R1 operates upstream of c-Jun N-terminal kinase/c-Jun, the central signal system of nerve fiber injury, and (iii) the failure of persistent reduction of activated c-Jun is linked to the failure of protection of dopaminergic SNC neurons by TNF-R1 ko.
authors: Institute of Pharmacology, Universitaetsklinikum Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105 Kiel, Germany.
authors: Jan
authors: J
authors: Wessig
authors: Stephan
authors: S
authors: Brecht
authors: Malte
authors: M
authors: Claussen
authors: Lutz
authors: L
authors: Roemer
authors: Mario
authors: M
authors: Goetz
authors: Paolo
authors: P
authors: Bigini
authors: Stephan
authors: S
authors: Schutze
authors: Thomas
authors: T
authors: Herdegen
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D019771:Axotomy; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D053331:Ectodysplasins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000293:injuries; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D020734:Parkinsonian Disorders; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013378:Substantia Nigra / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053331:Ectodysplasins; C506019:Eda protein, mouse; D008565:Membrane Proteins; D016755:Proto-Oncogene Proteins c-jun; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D048031:JNK Mitogen-Activated Protein Kinases