Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis.
Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis.
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DOI：
10.1371/journal.pone.0008130
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发表时间：
2009-12-02
期刊：
影响因子：
3.7
通讯作者：
Bonetto V
中科院分区：
文献类型：
--
作者：
Basso M;Samengo G;Nardo G;Massignan T;D'Alessandro G;Tartari S;Cantoni L;Marino M;Cheroni C;De Biasi S;Giordana MT;Strong MJ;Estevez AG;Salmona M;Bendotti C;Bonetto V
肌萎缩性侧索硬化症（ALS）是一种进行性致死性运动神经元疾病，蛋白质聚集被认为可能是其发病机制。然而，聚集蛋白成分的特征很差，因此对聚集在发病机制中的作用的认识是有限的。我们对家族性ALS （fALS）小鼠模型在不同疾病阶段的不溶性部分的蛋白质组成进行了蛋白质组学分析，作为蛋白质聚集的模型。我们已经在临床前阶段鉴定了几种富含洗涤剂不溶性部分的蛋白质，包括中间细丝、伴侣蛋白和线粒体蛋白。乌头酶、HSC70和亲环蛋白A在ALS患者脊髓的不溶性部分也显著富集。此外，我们发现小鼠和患者的HSP90中的大多数蛋白质都是酪氨酸硝化的。因此，我们研究了营养应激在fals样小鼠运动神经元-神经母细胞瘤（NSC-34）细胞系聚集形成中的作用。通过抑制一氧化氮的合成，不溶性蛋白，特别是乌头酶、HSC70、亲环蛋白A和SOD1的数量可以大幅减少。对细胞/小鼠模型和人体组织的不溶性组分的分析发现了新的易于聚集的蛋白质，并表明硝化应激有助于ALS中蛋白质聚集的形成。
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease, and protein aggregation has been proposed as a possible pathogenetic mechanism. However, the aggregate protein constituents are poorly characterized so knowledge on the role of aggregation in pathogenesis is limited. We carried out a proteomic analysis of the protein composition of the insoluble fraction, as a model of protein aggregates, from familial ALS (fALS) mouse model at different disease stages. We identified several proteins enriched in the detergent-insoluble fraction already at a preclinical stage, including intermediate filaments, chaperones and mitochondrial proteins. Aconitase, HSC70 and cyclophilin A were also significantly enriched in the insoluble fraction of spinal cords of ALS patients. Moreover, we found that the majority of proteins in mice and HSP90 in patients were tyrosine-nitrated. We therefore investigated the role of nitrative stress in aggregate formation in fALS-like murine motor neuron-neuroblastoma (NSC-34) cell lines. By inhibiting nitric oxide synthesis the amount of insoluble proteins, particularly aconitase, HSC70, cyclophilin A and SOD1 can be substantially reduced. Analysis of the insoluble fractions from cellular/mouse models and human tissues revealed novel aggregation-prone proteins and suggests that nitrative stress contribute to protein aggregate formation in ALS.
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影响因子：
2.9
作者：
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