Zhang Shengyao, Wan Guoran, Qiu Yu, Zhang Meng, Deng Hongmei, Wang Qiongfang, Hu Junyi, Gui Jie, Chen Dilong, Huang Boyue, Ran Jianhua
Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing, China.
Department of Neurology, University-Town Hospital of Chongqing Medical University, Chongqing, China.
NPJ Parkinsons Dis. 2025 Aug 11;11(1):237. doi: 10.1038/s41531-025-01099-5.
Parkinson's disease (PD), common neurodegenerative disorder, involves substantia nigra dopaminergic neuron loss and α-synuclein accumulation in Lewy bodies. While pathogenesis remains unclear, dysregulated urea metabolism may play a central role. This study detected elevated serum urea levels in PD patients with upregulated urea cycle enzymes. In MPTP-induced PD mice, urea accumulated in the substantia nigra and striatum, alongside increased activity of urea cycle enzymes (ODC1, ARG1, OTC) and urea transporter UT-B. Mechanistically, brain urea accumulation likely stems from imbalanced urea cycle activity and impaired UT-B-mediated clearance, with compensatory UT-B upregulation specifically in the substantia nigra. In vitro, MPTP-treated neuronal cells showed increased enzyme and UT-B expression, while high urea directly suppressed tyrosine hydroxylase (TH). Importantly, ODC1 knockdown reversed urea dysmetabolism, restored TH, and alleviated neuronal damage. These findings establish ODC1-mediated urea cycle dysregulation as a core metabolic feature of PD, proposing ODC1 or urea metabolism as novel therapeutic targets.
帕金森病（PD）是一种常见的神经退行性疾病，涉及黑质多巴胺能神经元丢失和路易小体中α-突触核蛋白的积累。虽然其发病机制尚不清楚，但尿素代谢失调可能起核心作用。本研究检测到尿素循环酶上调的PD患者血清尿素水平升高。在MPTP诱导的PD小鼠中，尿素在黑质和纹状体中积累，同时尿素循环酶（ODC1、ARG1、OTC）和尿素转运体UT-B的活性增加。从机制上讲，脑内尿素积累可能源于尿素循环活性失衡和UT-B介导的清除受损，黑质中UT-B特异性上调起代偿作用。在体外，MPTP处理的神经元细胞显示酶和UT-B表达增加，而高浓度尿素直接抑制酪氨酸羟化酶（TH）。重要的是，敲低ODC1可逆转尿素代谢紊乱，恢复TH，并减轻神经元损伤。这些发现确立了ODC1介导的尿素循环失调是PD的核心代谢特征，提出ODC1或尿素代谢作为新的治疗靶点。
