TARDBP公司
C9orf72
细胞质
应力颗粒
分子生物学
肌萎缩侧索硬化
生物
突变
免疫细胞化学
细胞生物学
突变体
污渍
SOD1
病理
基因
医学
遗传学
三核苷酸重复扩增
信使核糖核酸
内分泌学
等位基因
翻译(生物学)
疾病
作者
Margherita Lo Bello,Francesca Di Fini,Antonietta Notaro,Rossella Spataro,Francesca Luisa Conforti,Vincenzo La Bella
出处
期刊:Neurodegenerative Diseases
[S. Karger AG]
日期:2017-01-01
卷期号:17 (6): 292-303
被引量:23
摘要
Amyotrophic lateral sclerosis (ALS) shows a strong genetic basis, with SOD1, FUS, TARDBP, and C9ORF72 being the genes most frequently involved. This has allowed identification of asymptomatic mutation carriers, which may be of help in understanding the molecular changes preceding disease onset.We studied the cellular expression of FUS protein and the effect of heat-shock- and dithiothreitol-induced stress in fibroblasts from FUS P525L mutation carriers, healthy controls, and patients with sporadic ALS.Western blots and immunocytochemistry were performed to study the subcellular localization of FUS protein. Control and stressed cells were double stained with FUS and the stress marker TIA-R.Fibroblasts from healthy controls and sporadic ALS cases showed a prominent nuclear FUS expression. In the 2 FUS P525L mutation carriers, instead, most cells showed a protein localization in both nucleus and cytoplasm, or exclusively in the cytoplasm. Stress prompted the formation of cytoplasmic granules in all subjects and in sporadic ALS FUS mislocalization to the cytoplasm. Cytoplasmic FUS was recruited into stress granules, which showed a time-dependent decrease in all subjects. However, in the FUS P525L fibroblasts, the granules persisted longer, and they were more numerous than those detected in the cells from controls and sporadic ALS patients.We show that in fibroblasts of FUS P525L mutation carriers, FUS mislocalized to the cytoplasm where it redistributed into stress granules with likely a dose effect, i.e. a higher number of cells with granules, which persist longer, than in controls and ALS cases. These data represent an early molecular change occurring before ALS onset, suggesting a transient preaggregative state.
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