Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield, UK.
Department of Genetics, University of Leicester, Leicester, UK.
Acta Neuropathol Commun. 2017 Mar 16;5(1):23. doi: 10.1186/s40478-017-0424-x.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks a predictive and broadly applicable biomarker. Continued focus on mutation-specific upstream mechanisms has yet to predict disease progression in the clinic. Utilising cellular pathology common to the majority of ALS patients, we implemented an objective transcriptome-driven approach to develop noninvasive prognostic biomarkers for disease progression. Genes expressed in laser captured motor neurons in direct correlation (Spearman rank correlation, p < 0.01) with counts of neuropathology were developed into co-expression network modules. Screening modules using three gene sets representing rate of disease progression and upstream genetic association with ALS led to the prioritisation of a single module enriched for immune response to motor neuron degeneration. Genes in the network module are important for microglial activation and predict disease progression in genetically heterogeneous ALS cohorts: Expression of three genes in peripheral lymphocytes - LILRA2, ITGB2 and CEBPD - differentiate patients with rapid and slowly progressive disease, suggesting promise as a blood-derived biomarker. TREM2 is a member of the network module and the level of soluble TREM2 protein in cerebrospinal fluid is shown to predict survival when measured in late stage disease (Spearman rank correlation, p = 0.01). Our data-driven systems approach has, for the first time, directly linked microglia to the development of motor neuron pathology. LILRA2, ITGB2 and CEBPD represent peripherally accessible candidate biomarkers and TREM2 provides a broadly applicable therapeutic target for ALS.
肌萎缩侧索硬化症（ALS）是一种破坏性的神经退行性疾病，缺乏预测性和广泛适用的生物标志物。持续关注特定突变的上游机制尚未能够预测临床疾病进展。利用大多数 ALS 患者共有的细胞病理学，我们实施了一种客观的转录组驱动方法，以开发用于疾病进展的非侵入性预后生物标志物。与神经病理学计数直接相关（斯皮尔曼等级相关，p < 0.01）的激光捕获运动神经元中表达的基因被开发为共表达网络模块。使用三个代表疾病进展速度的基因集和与 ALS 上游遗传关联的基因集筛选模块，导致了一个富含对运动神经元退化的免疫反应的单一模块的优先级。网络模块中的基因对于小胶质细胞激活很重要，并可预测遗传异质性 ALS 队列中的疾病进展：外周淋巴细胞中三个基因的表达 - LILRA2、ITGB2 和 CEBPD - 可区分快速和缓慢进展的患者，这表明在外周血衍生生物标志物中有应用前景。TREM2 是网络模块的成员，脑脊液中可溶性 TREM2 蛋白的水平在晚期疾病中进行测量时，可预测生存（斯皮尔曼等级相关，p = 0.01）。我们的数据驱动系统方法首次将小胶质细胞与运动神经元病理学的发展直接联系起来。LILRA2、ITGB2 和 CEBPD 代表可在周围获得的候选生物标志物，TREM2 为 ALS 提供了广泛适用的治疗靶点。
