Finelli Mattéa J, Liu Kevin X, Wu Yixing, Oliver Peter L, Davies Kay E
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK
Hum Mol Genet. 2015 Jun 15;24(12):3529-44. doi: 10.1093/hmg/ddv104. Epub 2015 Mar 19.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5-10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元样细胞的丧失。RNA和DNA结合蛋白中的突变，即肉瘤融合蛋白（FUS）和43 kDa反式激活反应DNA结合蛋白（TDP - 43），分别导致5% - 10%的家族性ALS病例和1%的散发性ALS病例。重要的是，除了ALS之外，错误折叠的FUS或TDP - 43的聚集也是几种神经退行性疾病的特征，包括额颞叶变性。此外，FUS和TDP - 43靶基因的剪接失调以及线粒体异常与致病的FUS和TDP - 43突变体有关。虽然在了解这些蛋白质的功能方面已经取得了进展，但FUS和TDP - 43导致ALS的确切机制仍然未知。最近，我们发现，除了在ALS患者的脊髓中上调外，新型蛋白氧化抗性1（Oxr1）还能保护神经元免受氧化应激诱导的细胞凋亡。为了进一步了解Oxr1的功能，我们在此展示了该蛋白的首次相互作用研究。我们表明Oxr1与Fus和Tdp - 43结合，并且Fus和Tdp - 43中的某些与ALS相关的突变会影响它们与Oxr1的结合特性。我们进一步证明，在表达特定Fus和Tdp - 43突变体的细胞中增加Oxr1水平可改善与ALS相关的三个主要细胞特征：细胞质错误定位和聚集、线粒体基因的剪接变化以及线粒体缺陷。综上所述，这些发现表明OXR1可能对治疗具有TDP - 43病理特征的ALS和相关神经退行性疾病具有治疗益处。
