帕金森病(PD)在运动症状出现之前很久就开始在分子和细胞水平,但目前还没有用于诊断的早期分子生物标志物,预后预测,或监测治疗反应。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在其引入50多年后仍然是护理标准。这里,我们进行了大规模的表演,多组织,和多平台蛋白质组学研究,以确定新的生物标志物,用于PD的早期诊断和疾病监测。我们分析了4877例脑脊液,血浆,使用三种正交蛋白质组学方法,来自七个队列的参与者的尿液样本: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,数以百计的蛋白质在脑脊液中上调,血,或PD患者的尿液,患有DAT缺陷和REM睡眠行为障碍或失语症的前驱PD患者,以及LRRK2和GBA突变的非表现遗传携带者。我们在我们的分析中提名了多个新颖的命中作为早期PD的有希望的标记,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),谷氨酰氨基肽酶(ENPEP),WAP四二硫键核心结构域2(WFDC2),和其他人。DDC,催化多巴胺合成的最后一步,特别是作为一个新的打击与PD发病机制令人信服的联系。DDC在治疗初期PD的CSF和尿液中始终上调,前驱PD,和GBA或LRRK2载体参与者通过所有三种蛋白质组学方法。我们表明,CSFDDC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CSFDDC可能是一种有前途的诊断和预后标志物,可用于临床护理和转化研究。
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.