神经退行性疾病已经是医学上公认的难题。无数科学家和生物医药公司都曾在这一领域遭受挫折。然而，随着老龄化社会的进程，这类疾病成为了生命科学无法回避的一个问题。最近，中科院生物物理所的吴瑛课题组在著名期刊PLOS Genetics上发表了题为“FUS Interacts with HSP60 to Promote Mitochondrial Damage”的研究论文，报道了他们在这一领域的最新研究成果。在这项研究中，研究人员将目光放在了一种名为FUS（全称为fused in sarcoma/translocated in liposarcoma，FUS/TLS）的蛋白上，这是一个多功能的DNA/RNA结合蛋白，主要定位于细胞核，但可以在细胞核与细胞质中穿梭。FUS蛋白在RNA的转录、RNA的剪接和microRNA的加工等过程中发挥重要作用。FUS蛋白病是一组致命性、累及多种神经元的神经退行性疾病，包括FUS相关的额颞叶脑退行性病变/痴呆（frontotemporal lobar degeneration/dementia, FTLD-FUS）和运动神经元疾病，如非肌萎缩侧索硬化症（Amyotrophic Lateral Sclerosis, ALS-FUS）等。到目前为止，已经在FUS蛋白病的病例中发现50多个FUS基因的突变，然而，关于FUS蛋白如何造成神经元细胞死亡及其引起神经退行性疾病的细胞和分子机制尚不清楚。

       吴瑛课题组早期的研究工作成功地构建出FUS蛋白病的转基因果蝇模型，该模型可以很好地模拟FUS蛋白病的重要特征。对FUS转基因果蝇模型的深入研究发现，FUS蛋白的过表达可以引起线粒体片段化，造成线粒体损伤。利用果蝇遗传学筛选的方法，发现线粒体的分子伴侣HSP60可与FUS相互作用，RNAi沉默HSP60的果蝇同源基因可以在一定程度上挽救FUS转基因果蝇的神经退行性表型。进一步的免疫电镜、细胞和生化实验显示，FUS蛋白与HSP60蛋白直接相互作用；有意思的是，FUS蛋白可以直接定位到线粒体中，该过程由HSP60蛋白所介导。这些研究结果揭示了在病理或者FUS突变的情况下，FUS蛋白会过多的定位到线粒体中引发线粒体损伤，最终导致神经元细胞的死亡，并且提示线粒体损伤有可能成为治疗FUS蛋白病的新靶点。（生物谷Bioon.com）

生物股推荐的英文摘要：

PLOS Genetics    DOI: 10.1371/journal.pgen.1005357

FUS Interacts with HSP60 to Promote Mitochondrial Damage

FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.