Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic nigrostriatal neuron loss and brain accumulation of Lewy bodies, protein aggregates mainly composed of α-synuclein. We reported that mice deficient for NF-κB/c-Rel (c-rel-/-) develop a late-onset parkinsonism. At 18 months of age, c-rel-/- mice showed nigrostriatal degeneration and accumulation of α-synuclein aggregates associated with a motor impairment responsive to L-DOPA administration. Being c-Rel protein a transcriptional regulator for mitochondrial anti-oxidant and antiapoptotic factors, it has been inferred that its deficiency may affect the resilience of “energy demanding” nigral dopaminergic neurons to the aging process. PD patients manifest a prodromal syndrome that includes olfactory and gastrointestinal dysfunctions years before the frank degeneration of nigrostriatal neurons and appearance of motor symptoms. According to the Braak staging, the onset of non-motor and motor symptoms relates to progressive ascendant diffusion of α-synuclein pathology in the brain. The aim of this study was to identify whether c-rel-/- deficiency is associated with the onset of premotor signs of PD and spatio-temporal progression of cerebral α-synuclein deposition. Intestinal and olfactory functions, intestine and brain α-synuclein deposition as well as striatal alterations, were assessed in c-rel-/- and control mice from 2 to 18 months of age. From 2 months of age, c-rel-/- mice displayed intestinal constipation and increasing olfactory impairment. At 2 months, c-rel-/- mice exhibited a mild α-synuclein accumulation in the distal colon. Moreover, they developed an age-dependent deposition of fibrillary α-synuclein that, starting at 5 months from the olfactory bulbs, dorsal motor nucleus of vagus and locus coeruleus, reached the substantia nigra at 12 months. At this age, the α-synuclein pathology associated with a drop of dopamine transporter in the striatum that anticipated by 6 months the axonal degeneration. From 12 months onwards oxidative/nitrosative stress developed in the striatum in parallel with altered expression of mitochondrial homeostasis regulators in the substantia nigra. In c-rel-/- mice, reproducing a parkinsonian progressive pathology with non-motor and motor symptoms, a Braak-like pattern of brain ascending α-synuclein deposition occurs. The peculiar phenotype of c-rel-/- mice envisages a potential contribution of c-Rel dysregulation to the pathogenesis of PD.

中文翻译：

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NF-κB/c-Rel 缺乏导致小鼠帕金森病样前驱症状和进行性病理

帕金森病 (PD) 是最常见的神经退行性运动障碍，其特点是多巴胺能黑质纹状体神经元丢失和脑内路易小体聚集，蛋白质聚集体主要由 α-突触核蛋白组成。我们报道了缺乏 NF-κB/c-Rel (c-rel-/-) 的小鼠发展为迟发性帕金森症。在 18 个月大时，c-rel-/- 小鼠表现出黑质纹状体变性和 α-突触核蛋白聚集体的积累，这与对 L-DOPA 给药有反应的运动障碍相关。作为线粒体抗氧化和抗凋亡因子的转录调节因子，c-Rel 蛋白的缺乏可能会影响“能量需求”的黑质多巴胺能神经元对衰老过程的恢复能力。PD 患者在黑质纹状体神经元明显退化和运动症状出现之前数年就表现出包括嗅觉和胃肠功能障碍的前驱综合征。根据 Braak 分期，非运动和运动症状的发作与大脑中 α-突触核蛋白病理的进行性上升扩散有关。本研究的目的是确定 c-rel-/- 缺乏是否与 PD 运动前体征的出现和脑 α-突触核蛋白沉积的时空进展有关。在 2 至 18 个月大的 c-rel-/- 和对照小鼠中评估肠道和嗅觉功能、肠和脑 α-突触核蛋白沉积以及纹状体改变。从 2 个月大开始，c-rel-/- 小鼠表现出肠道便秘和嗅觉障碍增加。2个月时，c-rel-/- 小鼠在远端结肠中表现出轻度的 α-突触核蛋白积累。此外，他们开发了一种与年龄相关的纤维状 α-突触核蛋白沉积，从 5 个月开始，从嗅球、迷走神经背侧运动核和蓝斑核开始，在 12 个月时到达黑质。在这个年龄，α-突触核蛋白病理学与纹状体中多巴胺转运蛋白的下降相关，预计 6 个月时轴突退化。从 12 个月起，纹状体中出现氧化/亚硝化应激，同时黑质中线粒体稳态调节剂的表达发生改变。在 c-rel-/- 小鼠中，再现具有非运动和运动症状的帕金森病进行性病理，出现脑上行 α-突触核蛋白沉积的 Braak 样模式。