TDP-43 and Mitochondrial Dysfunction in ALS

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS），也称为Lou Gehrig病，是五种运动神经元疾病中最常见的，其特征是脑干和脊髓运动神经元的进行性神经退行性变。目前，ALS还没有治愈或有效的治疗方法。在大多数ALS病例中，病因不明。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编码的蛋白，即TAR dna结合蛋白43 (TDP-43)，被认为是大多数形式ALS退行性神经元的组织病理学标志（即神经元泛素化包裹体）的主要组成部分，越来越多的证据表明TDP-43在多种神经退行性疾病（包括ALS和额颞叶变性（FTLD））中起着关键作用。不幸的是，人们对TDP-43突变体如何导致神经退行性变知之甚少。有趣的是，在我们的初步研究中，我们还观察到表达突变体TDP-43的运动神经元细胞系线粒体生物能量学的显著损伤。由于线粒体功能障碍在ALS中起着重要作用，因此需要进一步深入研究突变体TDP-43对体内外原代运动神经元线粒体功能的影响，并探索突变体TDP-43导致线粒体功能障碍的潜在机制。在ALS和额颞叶变性（FTLD-U）中，TDP-43从细胞核转移到细胞质。不幸的是，很少有人尝试研究其亚细胞细胞器靶标。令人兴奋的是，我们的初步研究发现TDP-43可能存在于线粒体基质中。更重要的是，TDP-43与线粒体电子传递链关键的基质蛋白相互作用，并结合线粒体基因组编码的mRNA，表明TDP-43在调节线粒体功能中的直接作用。这些令人兴奋的发现强烈提示TDP-43可能通过其在线粒体中的特异性定位而损害线粒体功能，从而对ALS患者的神经元功能产生不利影响。因此，研究TDP-43如何被线粒体吸收，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。我们提出的研究将是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.