Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease

Abstract

Evidence from postmortem studies suggest an involvement of oxidative stress in the degeneration of dopaminergic neurons in Parkinson disease (PD) that have recently been shown to die by apoptosis, but the relationship between oxidative stress and apoptosis has not yet been elucidated. Activation of the transcription factor NF-B is associated with oxidative stress-induced apoptosis in several nonneuronal in vitro models. To investigate whether it may play a role in PD, we looked for the translocation of NF-B from the cytoplasm to the nucleus, evidence of its activation, in melanized neurons in the mesencephalon of postmortem human brain from five patients with idiopathic PD and seven matched control subjects. In PD patients, the proportion of dopaminergic neurons with immunoreactive NF-B in their nuclei was more than 70-fold that in control subjects. A possible relationship between the nuclear localization of NF-B in mesencephalic neurons of PD patients and oxidative stress in such neurons has been shown in vitro with primary cultures of rat mesencephalon, where translocation of NF-B is preceded by a transient production of free radicals during apoptosis induced by activation of the sphingomyelindependent signaling pathway with C 2

C-jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis

“…Serum deprivation increased endogenous ceramide levels in a two-peak manner: the first peak occurred very rapidly within the first hour and the second peak at 16 h after the apoptotic process had already been engaged. These data, together with the previous findings which demonstrate that a 6-h pulse of c 2 -ceramide treatment is sufficient to commit neurons to die (Hunot et al, 1997), suggest that the first ceramide peak could be responsible for apoptosis induction. This rapid and transient increase of ceramide may reflect an activation of sphingomyelinases, as seen after stimulation of non-neuronal cells with TNF-␣, Il-1␤ and Fas-ligand (for review see Kronke, 1997).…”

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

“…Indeed, induction of apoptosis has been correlated to NF-kB activation in a wide variety of systems including fibroblasts, 26,27 T cells, 28,29 ceramide-activated osteoblasts 30 and dopaminergic neurons derived from Parkinson's disease patients. 31 Cell fate towards apoptosis or survival after NF-kB activation seems to be cell type specific and/or dependent on cell environment. In NIH3T3 cells, we demonstrated that NF-kB is proapoptotic as cell treatment with NF-kB inhibitors decreased executioner caspase activity.…”

Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

“…Previous studies have reported that inappropriate regulation of NF-kB/Rel-mediated transcription is associated with pathological conditions including acute inflammatory responses, toxic/septic shock, acute phase reactions, atherosclerosis, radiation damage, and also with several neuropathologies (Grilli et al, 1993;Baldwin, 1996;O'Neill and Kaltschmidt, 1997). In post-mortem tissue from patients with neurodegenerative disease or cultured Expression profiling of NMDA receptor antagonists in brain M Marvanová et al neurons exposed to neurotoxic stimuli, increased NF-kB activity in cells has been reported (Kaltschmidt et al, 1995;Terai et al, 1996;Hunot et al, 1997). Furthermore, several studies have demonstrated that stimulation of both NMDA and non-NMDA glutamate receptors strongly stimulate NF-kB in vitro (Guerrini et al, 1995;Kaltschmidt et al, 1995).…”