Rutledge Jarod, Lehallier Benoit, Zarifkar Pardis, Losada Patricia Moran, Shahid-Besanti Marian, Western Dan, Gorijala Priyanka, Ryman Sephira, Yutsis Maya, Deutsch Gayle K, Mormino Elizabeth, Trelle Alexandra, Wagner Anthony D, Kerchner Geoffrey A, Tian Lu, Cruchaga Carlos, Henderson Victor W, Montine Thomas J, Borghammer Per, Wyss-Coray Tony, Poston Kathleen L
Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford University, Stanford, CA, USA.
Acta Neuropathol. 2024 Mar 11;147(1):52. doi: 10.1007/s00401-024-02706-0.
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始于分子和细胞水平，但目前尚无用于诊断、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——左旋多巴在引入50多年后仍是护理标准。在此，我们进行了一项大规模、多组织和多平台的蛋白质组学研究，以识别用于PD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，分析了来自七个队列参与者的4877份脑脊液、血浆和尿液样本：Olink邻近延伸分析、SomaScan适体沉淀分析和液相色谱-质谱蛋白质组学。我们发现，数百种蛋白质在PD患者、伴有多巴胺转运体（DAT）缺陷以及快速眼动睡眠行为障碍或嗅觉减退的前驱PD患者，以及LRRK2和GBA突变的未表现出症状的基因携带者的脑脊液、血液或尿液中上调。我们在分析中提名了多个新的发现作为早期PD的有前景的标志物，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）、富含WAP四二硫键结构域2（WFDC2）等。DDC催化多巴胺合成的最后一步，尤其作为一个与PD发病机制有令人信服的机制联系的新发现脱颖而出。通过所有三种蛋白质组学方法，DDC在未经治疗的PD、前驱PD以及GBA或LRRK2携带者参与者的脑脊液和尿液中持续上调。我们表明，脑脊液DDC水平与未经治疗的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，在临床护理和转化研究中均有用途。
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