Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.
Department of Neurorehabilitation Sciences, Casa Cura Policlinico (CCP), Milano, Italy.
Neurobiol Dis. 2020 Jun;139:104815. doi: 10.1016/j.nbd.2020.104815. Epub 2020 Feb 20.
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.
肌萎缩侧索硬化症（ALS）是一种致命的运动神经元疾病，目前尚无经过验证的生物标志物。先前的探索性研究已经在外周血单核细胞（PBMC）中鉴定出了一组候选蛋白生物标志物，其中包括肽基脯氨酰顺反异构酶 A（PPIA）、热休克同源蛋白 71 kDa（HSC70）、异质核核糖核蛋白 A2/B1（hnRNPA2B1）和 TDP-43。研究还发现，PPIA 在核糖核蛋白（RNP）复合物的组装和动态中起着关键作用，并与 TDP-43 相互作用。在 ALS 的 SOD1 小鼠模型中，缺乏 PPIA 会加速疾病进展，而 PBMC 中 PPIA 水平较低与早发性 ALS 相关。然而，PPIA 和其他候选蛋白生物标志物的诊断和预后价值尚未确定。我们分析了一组经过充分特征描述的 ALS 患者（n=93）、健康个体（n=104）和疾病对照组（n=111）的 PBMC 蛋白。我们使用了一种高度受控的样本处理程序，该程序意味着两步差异去污剂分步分离。我们发现，可溶性和不溶性部分中选定的 PBMC 蛋白的水平结合起来，具有区分 ALS 与对照组的高鉴别能力，其中 PPIA、hnRNPA2B1 和 TDP-43 与 ALS 最密切相关。我们还发现 ALS 中不溶性部分的蛋白质分配向增加的趋势，这与疾病表型恶化相关。特别是，低可溶性 PPIA 水平与六个月内死亡提前相关。总之，PPIA 是一种具有预后潜力的疾病修饰物。提示蛋白质和 RNA 稳态改变的 PBMC 蛋白是 ALS 的有前途的生物标志物，可用于诊断、预后和患者分层。
