Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the proteins and pathways involved in the pathophysiology are not fully understood. Even less is known about the preclinical disease phase. To uncover new ALS-related proteins and pathways, we performed a comparative proteomic analysis in cerebrospinal fluid (CSF) of asymptomatic (n = 14) and symptomatic (n = 14) ALS mutation carriers and sporadic ALS patients (n = 12) as well as post-mortem human spinal cord tissue (controls: n = 7, ALS, n = 8). Using a CSF-optimized proteomic workflow, we identified novel (e.g., UCHL1, MAP2, CAPG, GPNMB, HIST1H4A, HIST1H2B) and well-described (e.g., NEFL, NEFH, NEFM, CHIT1, CHI3L1) protein level changes in CSF of sporadic and genetic ALS patients with enrichment of proteins related to transcription, cell cycle and lipoprotein remodeling (total protein IDs: 2303). No significant alteration was observed in asymptomatic ALS mutation carriers representing the prodromal disease phase. We confirmed UCHL1, MAP2, CAPG and GPNMB as novel biomarker candidates for ALS in an independent validation cohort of patients (n = 117) using multiple reaction monitoring. In spinal cord tissue, 292 out of 6810 identified proteins were significantly changed in ALS with enrichment of proteins involved in mRNA splicing and of the neurofilament compartment. In conclusion, our proteomic data in asymptomatic ALS mutation carriers support the hypothesis of a sudden disease onset instead of a long preclinical phase. Both CSF and tissue proteomic data indicate transcriptional pathways to be amongst the most affected. UCHL1, MAP2 and GPNMB are promising ALS biomarker candidates which might provide additional value to the established neurofilaments in patient follow-up and clinical trials.

中文翻译：

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脑脊液和脊髓中的蛋白质组学提示UCHL1，MAP2和GPNMB作为生物标志物，并增强了肌萎缩性侧索硬化症转录途径的重要性。

肌萎缩性侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，涉及病理生理的蛋白质和途径尚不完全清楚。对临床前疾病阶段的了解甚至更少。为了发现新的ALS相关蛋白和途径，我们在无症状（n = 14）和有症状（n = 14）ALS突变携带者以及偶发性ALS患者（n = 12）的脑脊液（CSF）中进行了比较蛋白质组学分析作为验尸后的人脊髓组织（对照：n = 7，ALS，n = 8）。使用CSF优化的蛋白质组学工作流程，我们确定了散发性CSF中新的（例如UCHL1，MAP2，CAPG，GPNMB，HIST1H4A，HIST1H2B）和描述良好的（例如NEFL，NEFH，NEFM，CHIT1，CHI3L1）蛋白质水平变化和遗传性ALS患者中，富含与转录相关的蛋白质，细胞周期和脂蛋白重塑（总蛋白ID：2303）。在代表前驱疾病阶段的无症状ALS突变携带者中未观察到显着变化。我们使用多反应监测在独立验证的患者队列（n = 117）中证实了UCHL1，MAP2，CAPG和GPNMB是ALS的新型生物标志物候选物。在脊髓组织中，6810种经鉴定的蛋白质中的292种在ALS中发生了显着变化，这是由于参与mRNA剪接和神经丝区室的蛋白质富集所致。总之，我们的无症状ALS突变携带者蛋白质组学数据支持了疾病突然发作而不是长期的临床前期的假说。CSF和组织蛋白质组学数据均表明转录途径是受影响最严重的途径之一。UCHL1，