Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy.
Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia 25123, Italy.
Neurobiol Dis. 2023 May;180:106067. doi: 10.1016/j.nbd.2023.106067. Epub 2023 Mar 7.
Although Parkinson's disease (PD) key neuropathological hallmarks are well known, the underlying pathogenic mechanisms of the disease still need to be elucidated to identify innovative disease-modifying drugs and specific biomarkers. NF-κB transcription factors are involved in regulating several processes associated with neurodegeneration, such as neuroinflammation and cell death, that could be related to PD pathology. NF-κB/c-Rel deficient (c-rel) mice develop a progressive PD-like phenotype. The c-rel mice present both prodromal and motor symptoms as well as key neuropathological features, including nigrostriatal dopaminergic neurons degeneration, accumulation of pro-apoptotic NF-κB/RelA acetylated at the lysine 310 residue (Ac-RelA(lys310)) and progressive caudo-rostral brain deposition of alpha-synuclein. c-Rel inhibition can exacerbate MPTP-induced neurotoxicity in mice. These findings support the claim that misregulation of c-Rel protein may be implicated in PD pathophysiology. In this study, we aimed at evaluating c-Rel levels and DNA-binding activity in human brains and peripheral blood mononuclear cells (PBMCs) of sporadic PD patients. We analyzed c-Rel protein content and activity in frozen substantia nigra (SN) samples from post-mortem brains of 10 PD patients and 9 age-matched controls as well as in PBMCs from 72 PD patients and 40 age-matched controls. c-Rel DNA-binding was significantly lower and inversely correlated with Ac-RelA(lys310) content in post-mortem SN of sporadic PD cases, when compared to healthy controls. c-Rel DNA-binding activity was also reduced in PBMCs of followed-up PD subjects. The decrease of c-Rel activity in PBMCs from PD patients appeared to be independent from dopaminergic medication or disease progression, as it was evident even in early stage, drug-naïve patients. Remarkably, the levels of c-Rel protein were comparable in PD and control subjects, pointing out a putative role for post-translational modifications of the protein in c-Rel dysfunctions. These findings support that PD is characterized by the loss of NF-κB/c-Rel activity that potentially has a role in PD pathophysiology. Future studies will be aimed at addressing whether the reduction of c-Rel DNA-binding could constitute a novel biomarker for PD.
虽然帕金森病 (PD) 的主要神经病理学特征众所周知，但仍需要阐明疾病的潜在发病机制，以确定创新的疾病修饰药物和特定的生物标志物。NF-κB 转录因子参与调节与神经退行性变相关的多种过程，如神经炎症和细胞死亡，这些过程可能与 PD 病理学有关。NF-κB/c-Rel 缺陷 (c-rel) 小鼠会发展出类似 PD 的进行性表型。c-rel 小鼠表现出前驱期和运动症状以及关键的神经病理学特征，包括黑质纹状体多巴胺能神经元退化、促凋亡 NF-κB/RelA 在赖氨酸 310 残基乙酰化 (Ac-RelA(lys310)) 的积累以及逐渐向头侧的大脑中 α-突触核蛋白的沉积。c-Rel 抑制可加重 MPTP 诱导的小鼠神经毒性。这些发现支持这样一种观点，即 c-Rel 蛋白的失调可能与 PD 的病理生理学有关。在这项研究中，我们旨在评估散发性 PD 患者的人脑和外周血单核细胞 (PBMC) 中的 c-Rel 水平和 DNA 结合活性。我们分析了 10 名 PD 患者和 9 名年龄匹配的对照组死后大脑黑质 (SN) 样本以及 72 名 PD 患者和 40 名年龄匹配的对照组 PBMC 中的 c-Rel 蛋白含量和活性。与健康对照组相比，散发性 PD 病例死后 SN 中的 c-Rel DNA 结合显著降低且与 Ac-RelA(lys310)含量呈负相关。在随访的 PD 患者的 PBMC 中，c-Rel DNA 结合活性也降低了。PD 患者 PBMC 中 c-Rel 活性的降低似乎与多巴胺能药物或疾病进展无关，因为即使在早期、未经药物治疗的患者中也很明显。值得注意的是，PD 患者和对照组的 c-Rel 蛋白水平相当，表明蛋白质的翻译后修饰在 c-Rel 功能障碍中可能起作用。这些发现支持 PD 的特征是 NF-κB/c-Rel 活性的丧失，这可能在 PD 的病理生理学中起作用。未来的研究将旨在确定 c-Rel DNA 结合的减少是否可以作为 PD 的新型生物标志物。
