RESUMO
Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.
Assuntos
Envelhecimento/genética , Neurônios Dopaminérgicos/patologia , NF-kappa B/genética , Transtornos Parkinsonianos/genética , Substância Negra/patologia , Envelhecimento/metabolismo , Animais , Contagem de Células , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Ácido Homovanílico/metabolismo , Camundongos , Camundongos Knockout , Atividade Motora/genética , NF-kappa B/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Substância Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMO
Diverse nuclear factor-kappaB subunits mediate opposite effects of extracellular signals on neuron survival. While RelA is activated by neurotoxic agents, c-Rel drives neuroprotective effects. In brain ischaemia RelA and p50 factors rapidly activate, but how they associate with c-Rel to form active dimers and contribute to the changes in diverse dimer activation for neuron susceptibility is unknown. We show that in both cortical neurons exposed to oxygen glucose deprivation (OGD) and mice subjected to brain ischaemia, activation of p50/RelA was associated with inhibition of c-Rel/RelA dimer and no change p50/c-Rel. Targeting c-Rel and RelA expression revealed that c-Rel dimers reduced while p50/RelA enhanced neuronal susceptibility to anoxia. Activation of p50/RelA complex is known to induce the pro-apoptotic Bim and Noxa genes. We now show that c-Rel-containing dimers, p50/c-Rel and RelA/c-Rel, but not p50/RelA, promoted Bcl-xL transcription. Accordingly, the OGD exposure induced Bim, but reduced Bcl-xL promoter activity and decreased the content of endogenous Bcl-xL protein. These findings demonstrate that within the same neuronal cell, the balance between activation of p50/RelA and c-Rel-containing complexes fine tunes the threshold of neuron vulnerability to the ischaemic insult. Selective targeting of different dimers will unravel new approaches to limit ischaemia-associated apoptosis.
Assuntos
Infarto da Artéria Cerebral Média/patologia , Subunidade p50 de NF-kappa B/metabolismo , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-rel/fisiologia , Fator de Transcrição RelA/fisiologia , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Regulação da Expressão Gênica/fisiologia , Glucose/deficiência , Humanos , Hipóxia , Imunoprecipitação/métodos , Marcação In Situ das Extremidades Cortadas , Infarto da Artéria Cerebral Média/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Subunidade p50 de NF-kappa B/genética , Neuroblastoma , Proteínas Proto-Oncogênicas c-rel/genética , RNA Interferente Pequeno/farmacologia , Fator de Transcrição RelA/genética , Transfecção/métodos , Proteína bcl-X/metabolismoRESUMO
Nuclear factor-kappaB (NF-kappaB) is a dimeric transcription factor composed of five members, p50, RelA/p65, c-Rel, RelB, and p52 that can diversely combine to form the active transcriptional dimer. NF-kappaB controls the expression of genes that regulate a broad range of biological processes in the central nervous system such as synaptic plasticity, neurogenesis, and differentiation. Although NF-kappaB is essential for neuron survival and its activation may protect neurons against oxidative-stresses or ischemia-induced neurodegeneration, NF-kappaB activation can contribute to inflammatory reactions and apoptotic cell death after brain injury and stroke. It was proposed that the death or survival of neurons might depend on the cell type and the timing of NF-kappaB activation. We here discuss recent evidence suggesting that within the same neuronal cell, activation of diverse NF-kappaB dimers drives opposite effects on neuronal survival. Unbalanced activation of NF-kappaB p50/RelA dimer over c-Rel-containing complexes contributes to cell death secondary to the ischemic insult. While p50/RelA acts as transcriptional inducer of Bcl-2 family proapoptotic Bim and Noxa genes, c-Rel dimers specifically promote transcription of antiapototic Bcl-xL gene. Changes in the nuclear content of c-Rel dimers strongly affect the threshold of neuron vulnerability to ischemic insult and agents, likewise leptin, activating a NF-kappaB/c-Rel-dependent transcription elicit neuroprotection in animal models of brain ischemia.