TDP-43 and Mitochondrial Dysfunction in ALS

描述（由申请人提供）：肌萎缩侧索硬化症（ALS），也称为Lou Gehrig病，是五种运动神经元疾病中最常见的一种，其特征在于脑干和脊髓中运动神经元的进行性神经变性。目前，ALS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SOD 1和TARDBP等几个基因的突变。由TARDBP编码的蛋白质，即TAR DNA结合蛋白43（TDP-43），被鉴定为组织病理学标志的主要组分，即，在大多数形式的ALS中，神经元泛素化内含物是变性神经元的一部分，越来越多的证据表明TDP-43在包括ALS和额颞叶变性（FTLD）在内的多种神经变性疾病中起关键作用。不幸的是，TDP-43突变体如何导致神经变性还知之甚少。有趣的是，在我们的初步研究中，我们还观察到在表达突变TDP-43的运动神经元细胞系中线粒体生物能量学的显著损害。由于线粒体功能障碍在ALS中起着重要作用，因此应进行进一步更详细的研究，以评估突变TDP-43对体外和体内初级运动神经元线粒体功能的影响，并探索突变TDP- 43引起线粒体功能障碍的潜在潜在机制。TDP-43在ALS和额颞叶变性（FTLD-U）中从细胞核易位到细胞质。不幸的是，很少有人尝试研究其亚细胞器的目标（S）。令人兴奋的是，我们的初步研究发现TDP-43可以存在于线粒体基质中。而且，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质相互作用，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。所有这些令人兴奋的发现强烈表明TDP-43可能通过其在线粒体中的特异性定位而损害线粒体功能，这对ALS中的神经元功能产生不利影响。因此，重要的是研究TDP-43如何被线粒体摄取，并测试TDP-43线粒体定位是否是其对线粒体和神经元的毒性所必需的。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在调节线粒体功能中的新作用，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.