Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease for which there are no validated biomarkers. Previous exploratory studies have identified a panel of candidate protein biomarkers in peripheral blood mononuclear cells (PBMCs) that include peptidyl-prolyl cis-trans isomerase A (PPIA), heat shock cognate protein 71 kDa (HSC70), heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) and TDP-43. It has also been found that PPIA plays a key role in the assembly and dynamics of ribonucleoprotein (RNP) complexes and interacts with TDP-43. Its absence accelerates disease progression in a SOD1 mouse model of ALS, and low levels of PPIA in PBMCs are associated with early-onset ALS. However, the diagnostic and prognostic values of PPIA and the other candidate protein biomarkers have not been established. We analyzed the PBMC proteins in a well-characterized cohort of ALS patients (n=93), healthy individuals (n=104) and disease controls (n=111). We used a highly controlled sample processing procedure that implies two-step differential detergent fractionation. We found that the levels of the selected PBMC proteins in the soluble and insoluble fraction, combined, have a high discriminatory power for distinguishing ALS from controls, with PPIA, hnRNPA2B1 and TDP-43 being the proteins most closely associated with ALS. We also found a shift toward increased protein partitioning in the insoluble fraction in ALS and this correlated with a worse disease phenotype. In particular, low PPIA soluble levels were associated with six months earlier death. In conclusion, PPIA is a disease modifier with prognostic potential. PBMC proteins indicative of alterations in protein and RNA homeostasis are promising biomarkers of ALS, for diagnosis, prognosis and patient stratification.

中文翻译：

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PBMC蛋白在肌萎缩性侧索硬化中的诊断和预后价值。

肌萎缩性侧索硬化症（ALS）是一种致命的运动神经元疾病，尚无经过验证的生物标记物。先前的探索性研究已经确定了外周血单核细胞（PBMC）中的一组候选蛋白质生物标志物，包括肽基脯氨酰顺反异构酶A（PPIA），热休克同源蛋白质71 kDa（HSC70），异质核糖核糖核酸A2 / B1（ hnRNPA2B1）和TDP-43。还发现PPIA在核糖核蛋白（RNP）复合物的组装和动力学中起关键作用，并与TDP-43相互作用。它的缺失加速了ALS的SOD1小鼠模型的疾病进展，PBMC中低水平的PPIA与早发性ALS相关。但是，PPIA和其他候选蛋白质生物标志物的诊断和预后价值尚未确定。我们分析了特征明确的ALS患者（n = 93），健康个体（n = 104）和疾病对照（n = 111）的队列中的PBMC蛋白。我们使用了高度受控的样品处理程序，该程序包含两步差分洗涤剂分级分离。我们发现，可溶和不可溶级分中选定的PBMC蛋白的水平相结合，具有很高的区分力，可将ALS与对照区分开，其中PPIA，hnRNPA2B1和TDP-43是与ALS最相关的蛋白。我们还发现ALS的不溶部分中的蛋白质分配增加，这与疾病表型恶化有关。特别是低PPIA可溶性水平与六个月前死亡有关。总之，PPIA是具有预后潜力的疾病改良剂。