Wang Qinqin, Yu Hao, Yuan Xunan, Li Ruolin, Li Xuezhi, Yin Shu, Ma Xiaodan, Wang Xinmiao
Institute of Mental Health, Jining Medical University, Jining, China.
Affiliated Hospital of Jining Medical University, Jining, Shandong, China.
CNS Neurosci Ther. 2025 Jun;31(6):e70472. doi: 10.1111/cns.70472.
Parkinson's disease (PD), the second most prevalent age-associated neurodegenerative disorder, is characterized by the degeneration and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SN). Among the intricate pathophysiological processes of PD, chronic neuroinflammation has emerged as a pivotal hallmark in the pathogenesis of PD. The aminoacyl tRNA synthetase complex has been reported to play an important role in modulating the immune response and associated diseases. Nevertheless, the specific functions and implications of the complex in PD remain largely unclear.
Enzyme-linked immunosorbent assay (ELISA) was used to investigate levels of AIMP1 and TNF-α. An in vivo PD model was constructed by administering 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP). Pole test was performed to assess the motor function of mice. DA neuron survival and microglia activation were detected by immunofluorescence. Western blot and qPCR were used to detect the levels of tyrosine hydroxylase (TH) and inflammatory cytokines. RNA-Seq analysis was performed to explore possible mechanisms.
The levels of AIMP1, a co-factor of the aminoacyl tRNA synthetase complex, were significantly elevated in the blood of PD patients. Aimp1 knockout or knockdown remarkably improved the viability of DA neurons in the MPTP-induced mouse model of PD. Aimp1 deficiency reduced microglial activation in PD mice. RNA-Seq analysis revealed that AIMP1 promoted microglial inflammatory response. Moreover, the AIMP1-induced microglial activation was CD23 dependent.
Collectively, our findings indicate that AIMP1 derived from DA neurons exacerbates neuroinflammation, promotes the death of DA neurons and contributes to the development of PD. This study offers novel insights into the molecular mechanisms underlying PD and blocking the AIMP1-CD23 signaling pathway potentially serves as a therapeutic strategy for PD.
帕金森病（PD）是第二常见的与年龄相关的神经退行性疾病，其特征是黑质致密部（SN）中多巴胺能（DA）神经元的变性和丧失。在PD复杂的病理生理过程中，慢性神经炎症已成为PD发病机制的关键标志。据报道，氨酰tRNA合成酶复合体在调节免疫反应及相关疾病中起重要作用。然而，该复合体在PD中的具体功能和意义仍 largely不清楚。
采用酶联免疫吸附测定（ELISA）检测AIMP1和TNF-α水平。通过给小鼠注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）构建体内PD模型。用1-甲基-4-苯基吡啶鎓（MPP）处理SH-SY5Y细胞建立PD细胞模型。进行杆试验评估小鼠的运动功能。通过免疫荧光检测DA神经元存活和小胶质细胞活化。采用蛋白质印迹法和qPCR检测酪氨酸羟化酶（TH）和炎性细胞因子水平。进行RNA测序分析以探索可能的机制。
氨酰tRNA合成酶复合体的辅助因子AIMP1水平在PD患者血液中显著升高。Aimp1基因敲除或敲低显著提高了MPTP诱导的PD小鼠模型中DA神经元的活力。Aimp1缺陷减少了PD小鼠中小胶质细胞的活化。RNA测序分析表明AIMP1促进小胶质细胞炎症反应。此外，AIMP1诱导的小胶质细胞活化依赖于CD23。
总体而言，我们的研究结果表明，源自DA神经元的AIMP1会加剧神经炎症，促进DA神经元死亡并导致PD的发展。本研究为PD潜在的分子机制提供了新见解，阻断AIMP1-CD23信号通路可能成为PD的一种治疗策略。
