VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology
VAPB ER-Aggregates, A Possible New Biomarker in ALS Pathology
复制标题
DOI：
10.3390/cells9010164
复制
发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Galleri, Grazia
中科院分区：
文献类型：
--
作者：
Cadoni, Maria Piera L.;Biggio, Maria Luigia;Galleri, Grazia
编码囊泡相关膜蛋白相关蛋白B（VAP B）的基因中的点突变（P56 S）导致常染色体显性形式的肌萎缩性侧索硬化（ALS），归类为ALS-8。突变VAPB的特征在于ER相关的聚集体，导致ER结构的完全重组。越来越多的证据表明VAPB参与ALS的病理机制。事实上，许多研究表明，VAPB改变也在散发性ALS（sALS），并显示其聚集体的存在下，当其他ALS相关基因突变。最近，在外周血单核细胞（PBMC）中鉴定新的生物标志物已被提出作为研究ALS的一个很好的非侵入性选择。在这里，我们评估VAPB作为一个可能的ALS病理标志物分析sALS患者的PBMC。免疫荧光分析（IFA）显示了一种特殊的模式VAPB聚集体在sALS，不明显的健康对照（HC）的受试者和帕金森病（PD）的PBMC。这种特定的模式使我们假设VAPB可能在sALS中错误折叠。通过流式细胞术测定（FCA）间接证实的数据显示sALS中VAPB荧光信号减少。然而，我们的观察结果与VAPB基因突变或基因表达改变的存在无关。我们的研究进一步证明了VAPB在ALS中作为诊断生物标志物的作用。
A point mutation (P56S) in the gene-encoding vesicle-associated membrane-protein-associated protein B (VAPB) leads to an autosomal-dominant form of amyotrophic lateral sclerosis (ALS), classified as ALS-8. The mutant VAPB is characterized by ER-associated aggregates that lead to a complete reorganization of ER structures. Growing evidences suggest VAPB involvement in ALS pathomechanisms. In fact, numerous studies demonstrated VAPB alteration also in sporadic ALS (sALS) and showed the presence of its aggregates when others ALS-related gene are mutant. Recently, the identification of new biomarkers in peripheral blood mononuclear cells (PBMCs) has been proposed as a good noninvasive option for studying ALS. Here, we evaluated VAPB as a possible ALS pathologic marker analyzing PBMCs of sALS patients. Immunofluorescence analysis (IFA) showed a peculiar pattern of VAPB aggregates in sALS, not evident in healthy control (HC) subjects and in Parkinson's disease (PD) PBMCs. This specific pattern led us to suppose that VAPB could be misfolded in sALS. The data indirectly confirmed by flow cytometry assay (FCA) showed a reduction of VAPB fluorescent signals in sALS. However, our observations were not associated with the presence of a genetic mutation or altered gene expression of VAPB. Our study brings further evidences of the VAPB role in ALS as a diagnostic biomarker.