TDP-43 and Mitochondrial Dysfunction in ALS

描述(申请人提供)：肌萎缩侧索硬化症(ALS)，又称Lou Gehrig病，是五种运动神经元病中最常见的一种，其特征是脑干和脊髓运动神经元进行性神经变性。目前，ALS还没有治愈或有效的治疗方法。在大多数ALS病例中，病因尚不清楚。不到10%的ALS病例是家族性的，涉及SOD1和TARDBP等几个基因的突变。TARDBP编码的TAR DNA结合蛋白43(TDP-43)被认为是大多数ALS退行性神经元的组织病理学标志，即神经元泛素化包涵体的主要成分，越来越多的证据表明TDP-43在包括ALS和额颞叶变性(FTLD)在内的多种神经退行性疾病中起着关键作用。不幸的是，TDP-43突变是如何导致神经退行性变的还知之甚少。有趣的是，在我们的初步研究中，我们还观察到表达突变TDP-43的运动神经元细胞系的线粒体生物能量学显著受损。由于线粒体功能障碍在肌萎缩侧索硬化症的发病机制中起着非常重要的作用，因此有必要进一步深入研究突变型TDP-43在体内外对原代运动神经元线粒体功能的影响，并探讨突变型TDP-43导致线粒体功能障碍的可能机制。在ALS和额颞叶变性(FTLD-U)中，TDP-43从胞核向胞浆转位。不幸的是，很少有人尝试研究它的亚细胞器靶标(S)。令人兴奋的是，我们的初步研究发现TDP-43可能存在于线粒体的基质中。更重要的是，TDP-43与线粒体电子传递链关键的面向基质的蛋白相互作用，并与线粒体基因组编码的mRNA结合，表明TDP-43在调节线粒体功能方面发挥了直接作用。所有这些令人兴奋的发现有力地表明，TDP-43可能通过其在线粒体中的特异性定位而损害线粒体的功能，从而对ALS的神经元功能产生不利影响。因此，研究TDP-43是如何被线粒体摄取的，并测试TDP-43对线粒体和神经元的毒性是否需要线粒体定位是很重要的。我们的研究将是TDP-43线粒体输入以及TDP-43诱导的线粒体功能障碍的第一个系统和机制研究。我们提出的研究将揭示TDP-43在线粒体功能调节中的新作用，并可能为ALS提供新的治疗靶点。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is the most common of the five motor neuron diseases characterized by progressive neurodegeneration of motor neurons in the brain stem and spinal cord. Currently, there is no cure or effective treatment for ALS. The cause of disease is unknown in the majority of ALS cases. Less than 10% of ALS cases are familial, involving mutations in several genes such as SOD1 and TARDBP. The protein encoded by TARDBP, i.e. TAR DNA-binding protein 43 (TDP-43), was identified as a major component of the histopathological hallmark, i.e., neuronal ubiquitinated inclusions, of degenerating neurons in most forms of ALS and increasing evidence suggests a critical role of TDP-43 in diverse neurodegenerative diseases including ALS and frontotemporal lobar degeneration (FTLD). Unfortunately, how TDP-43 mutant causes neurodegeneration is poorly understood. Interestingly, in our preliminary studies, we also observed significant impairment of mitochondrial bioenergetics in motor neuronal cell lines expressing mutant TDP-43. As mitochondrial dysfunction plays a prominent role in ALS, further more detailed studies should be performed to assess the effect of mutant TDP-43 on mitochondrial function in primary motor neurons in vitro and in vivo, and explore potential underlying mechanisms by which mutant TDP- 43 cause mitochondrial dysfunction. TDP-43 translocates from the nucleus to cytoplasm in of ALS and frontotemporal lobar degeneration (FTLD-U). Unfortunately, few attempt has been taken to investigate its subcellular organelle target(s). Excitingly, our pilot studies found that TDP-43 could be present in the matrix of mitochondria. And, more importantly, TDP-43 interacts with a matrix facing protein critical for mitochondrial electron transport chain, and binds mitochondrial genome encoded mRNA, indicating a direct role of TDP-43 in regulating mitochondrial function. All these exciting finding strongly suggest that TDP-43 may impair mitochondrial function through its specific localization in mitochondria which adversely affects neuronal functions in ALS. Thus, it is important to investigate how TDP-43 is taken up by mitochondria and test whether TDP-43 mitochondrial localization is required for its toxicity on mitochondria and neurons. Our proposed study will be the first systematic and mechanistic study of TDP-43 mitochondrial import as well as TDP-43 induced mitochondrial dysfunction. Our proposed studies will reveal a novel role of TDP-43 in the regulation of mitochondrial function and likely provide novel therapeutic targets for ALS.