The heterogeneity of Parkinson’s disease (PD) has been recognized in clinical, with patients categorized into distinct subsets based on motor phenotype, such as tremor-dominant PD (TD), postural instability and gait difficulty-dominant PD (PIGD) and mixed PD (Mix). Despite this categorization, the underlying mechanisms of this heterogeneity remain poorly understood, and there is no personalized effective treatment for each PD subtype. To address this, a rat model for PD subtypes was established by unilateral stereotaxic injection of 6-OHDA, followed by cluster analysis of behavioral data. The serum neurofilament light chain (NfL) and uric acid (UA) levels as well as alterations in brain autonomic activity in rats were consistent with clinical patients, and metabolomics results showed that more than 70% of the metabolites in the serum of different subtypes of PD rats and clinical patients appeared to be consistently altered. Further transcriptomic analysis by RNA-seq has elucidated that the development of PD subtypes is associated with altered gene expression in neurotransmitter, neuronal damage in the central or peripheral nervous system, and lipid metabolism. In addition, based on the subtype-specific differentially expressed genes, 25 potential drug candidates were identified. Notably, the Alox15 inhibitor baicalein showed a greater efficacy on Mix rats, highlighting the possibility of selecting targeted treatments for well-defined individuals.

帕金森病 （PD） 的异质性已在临床上得到认可，患者根据运动表型分为不同的亚群，例如震颤显性 PD （TD）、姿势不稳和步态困难显性 PD （PIGD） 和混合性 PD （Mix）。尽管有这种分类，但这种异质性的潜在机制仍然知之甚少，并且没有针对每种 PD 亚型的个性化有效治疗。为了解决这个问题，通过单侧立体定位注射 6-OHDA 建立了 PD 亚型大鼠模型，然后对行为数据进行聚类分析。大鼠血清神经丝轻链 （NfL） 和尿酸 （UA） 水平以及脑自主神经活动的改变与临床患者一致，代谢组学结果显示，不同亚型 PD 大鼠和临床患者血清中超过 70% 的代谢物似乎持续改变。通过 RNA-seq 进行的进一步转录组学分析阐明，PD 亚型的发展与神经递质基因表达的改变、中枢或周围神经系统的神经元损伤以及脂质代谢有关。此外，根据亚型特异性差异表达基因，确定了 25 种潜在的候选药物。值得注意的是，Alox15 抑制剂黄芩素对 Mix 大鼠显示出更大的疗效，突出了为定义明确的个体选择靶向治疗的可能性。