Parkinson’s disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research—l-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography–mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as l-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

帕金森病 (PD) 早在运动症状出现之前就在分子和细胞水平上开始，但目前还没有用于诊断、预后预测或监测治疗反应的早期分子生物标志物。生物标志物的缺乏极大地阻碍了患者护理和转化研究——l - DOPA 在引入 50 多年后仍然是护理标准。在这里，我们进行了大规模、多组织、多平台的蛋白质组学研究，以确定用于帕金森病早期诊断和疾病监测的新生物标志物。我们使用三种正交蛋白质组学方法分析了七个队列参与者的 4877 份脑脊液、血浆和尿液样本：Olink 邻近延伸测定、SomaScan 适体沉淀测定和液相色谱-质谱蛋白质组学。我们发现，PD 患者、患有 DAT 缺陷和 REM 睡眠行为障碍或嗅觉丧失的前驱 PD 患者以及 LRRK2 和 GBA 突变的非表现性遗传携带者的脑脊液、血液或尿液中数百种蛋白质上调。我们在分析中提名了多个新的命中作为早期 PD 有希望的标志物，包括多巴脱羧酶 (DDC)，也称为L-芳香酸脱羧酶 (AADC)、硫酸酯酶修饰因子 1 (SUMF1)、二肽基肽酶 2/7 (DPP7) )、谷氨酰氨肽酶 (ENPEP)、WAP 四二硫键核心结构域 2 (WFDC2) 等。 DDC 能够催化多巴胺合成的最后一步，它作为与 PD 发病机制具有令人信服的机制联系的新药而脱颖而出。通过所有三种蛋白质组学方法，DDC 在初治 PD、前驱 PD 和 GBA 或 LRRK2 携带者参与者的 CSF 和尿液中持续上调。我们发现，CSF DDC 水平与初治 PD 患者的临床症状严重程度相关，可用于准确诊断 PD 和前驱 PD。这表明尿液和脑脊液 DDC 可能是一种有前景的诊断和预后标志物，可用于临床护理和转化研究。