Chronic constipation is one of the most prominent prodromal symptoms in Parkinson’s disease (PD), and Lewy bodies, enriched with aggregated α-Synuclein (α-Syn), propagation from the gut into the brain has been proposed to play a key role in PD etiopathogenesis. BDNF (Brain-derived neurotrophic factor) and Netrin-1 promote both neuronal survival and regulate the gut functions. We hypothesize that C/EBPβ represses BDNF and Netrin-1 in peripheral nervous system and central nervous system, contributing to GI tract and brain malfunctions in PD. To test the hypothesis, we performed the studies in both human PD gut tissues and BDNF or Netrin-1 gut conditional KO mice models. Lewy bodies with α-Syn aggregation and neuro-inflammation were measured in the colon and brain samples from PD patients and healthy controls and rotenone or vehicle-treated WT and CEBPβ (+/-) mice. We show that both BDNF and Netrin-1 are strongly decreased in the brain and the gut of PD patients, and conditional KO of these trophic factors in the gut elicits dopaminergic neuronal loss, constipation and motor dysfunctions. Interestingly, the inflammation and oxidative stress-induced transcription factor C/EBPβ acts as a robust repressor for both BDNF and Netrin-1 and suppresses the expression of trophic factors, and its levels inversely correlate with BDNF and Netrin-1 in PD patients. Our findings support that gut inflammation induces C/EBPβ activation that leads to both BDNF and Netrin-1 reduction and triggers PD non-motor and motor symptoms. Possibly, C/EBPβ-mediated biological events might be early diagnostic biomarkers for PD.

慢性便秘是帕金森病 (PD) 中最突出的前驱症状之一，富含聚集的 α-突触核蛋白 (α-Syn) 的路易小体从肠道传播到大脑已被提议在 PD 中发挥关键作用发病机制。BDNF（脑源性神经营养因子）和 Netrin-1 促进神经元存活并调节肠道功能。我们假设 C/EBPβ 在外周神经系统和中枢神经系统中抑制 BDNF 和 Netrin-1，导致 PD 中的胃肠道和脑功能障碍。为了验证这一假设，我们在人类 PD 肠道组织和 BDNF 或 Netrin-1 肠道条件性 KO 小鼠模型中进行了研究。在来自 PD 患者和健康对照以及鱼藤酮或载体处理的 WT 和 CEBPβ (+/-) 小鼠的结肠和脑样本中测量了具有 α-Syn 聚集和神经炎症的路易体。我们表明 BDNF 和 Netrin-1 在 PD 患者的大脑和肠道中均显着降低，并且肠道中这些营养因子的条件性 KO 会引起多巴胺能神经元丢失、便秘和运动功能障碍。有趣的是，炎症和氧化应激诱导的转录因子 C/EBPβ 作为 BDNF 和 Netrin-1 的强大抑制因子并抑制营养因子的表达，其水平与 PD 患者的 BDNF 和 Netrin-1 呈负相关。我们的研究结果支持肠道炎症诱导 C/EBPβ 激活，导致 BDNF 和 Netrin-1 减少并触发 PD 非运动和运动症状。