Elucidating the Mechanisms Underlying Mutant TDP43-induced Neurodegeneration

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是最常见的运动神经元疾病，尽管Jean-Martin Charcot在100多年前首次描述了它，但仍然没有有效的治疗方法来治疗这种疾病典型的最终致命的虚弱和肌肉萎缩。同样，我们治疗额颞部痴呆(FTD)的能力也受到严重限制。FTD是65岁以下人群中第二种最常见的痴呆症。尽管临床上存在差异，但大多数ALS和最常见的FTD类型都有一个共同的病理特征，即43 kDa的TAR DNA结合蛋白(TDP-43)沉积。TDP-43编码基因(TARDBP)突变的鉴定及其与家族性ALS和FTD的关系表明TDP-43在疾病的发病机制中起着不可或缺的作用。这项建议探索了突变TDP43诱导神经元丢失的细胞机制，为开发可以预防ALS、FTD和其他以TDP-43积聚为标志的神经退行性疾病的治疗方法奠定了基础。在初步研究中，我们建立了一个忠实的TDP43蛋白病变的神经元模型，并验证了该系统在体外概括了疾病的基本特征。此外，我们证明了与家族性ALS相关的TARDBP突变能够通过TDP-43从通常集中的细胞核到细胞质的错误定位而导致神经元毒性。ALS和FTD患者神经元变性的特点是TDP-43的胞浆重新分布相同，证实了这一现象的重要性，并直接与疾病的发病机制有关。特定的目标1和2集中在突变TDP-43细胞质重新分布的潜在机制上。有趣的是，TARDBP的突变总是会导致运动神经元变性的ALS症状，但只有极少数出现皮质神经元病理的痴呆，这表明运动神经元对突变的TDP-43有选择性的易感性。在具体目标3中，我描述了运动神经元对突变型TDP-43的特殊敏感性。该项目的基本目标是定义突变TDP43介导的神经变性所涉及的途径，最终目的是设计具有预防或逆转疾病进展的能力的治疗方法。由于TDP-43沉积是自发性和家族性ALS的基本特征，也是FTD最常见的病理亚型，因此研究TDP-43‘S在疾病发病机制中的作用对于我们最终开发有效的治疗方法至关重要。作为该项目的首席研究员，我在神经学和神经科学方面有很强的背景，在追求这一目标的过程中，我将得到一个主要赞助商、一个专门的咨询委员会和两个机构(格莱斯顿研究所和加州大学旧金山分校)的支持。这份申请书中描述的研究将为我在神经退行性疾病领域的职业生涯奠定基础。此外，随着这个奖项的获得，我将获得机会获得技能、知识、指导和经验，成为一名成功和独立的内科科学家。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, and despite its initial description over 100 years ago by Jean-Martin Charcot, there remains no effective therapy for the ultimately fatal weakness and muscle atrophy typical of the disorder. Likewise, our ability to treat patients with frontotemporal dementia (FTD), the second most common type of dementia in individuals under the age of 65, is severely limited. Despite their clinical disparity, the majority of ALS and the most prevalent type of FTD share a common pathology marked by the deposition of the TAR DNA binding protein of 43 kDa (TDP-43). The identification of mutations within the gene encoding TDP-43 (TARDBP) and their association with familial ALS and FTD suggested that TDP-43 plays an integral role in disease pathogenesis. This proposal explores the cellular mechanisms responsible for mutant TDP43-induced neuronal loss, laying the foundation for the development of therapies that can prevent ALS, FTD, and other neurodegenerative conditions marked by TDP- 43 accumulation. In preliminary studies, we established a faithful neuronal model of TDP43-proteinopathies and verified that this system recapitulates essential features of disease in vitro. Furthermore, we demonstrated that a mutation in TARDBP associated with familial ALS is capable of causing neuronal toxicity through the mislocalization of TDP-43 from the nucleus, where it is normally concentrated, to the cytoplasm. An identical cytoplasmic redistribution of TDP-43 is characteristic of degenerating neurons from patients with ALS and FTD, confirming the significance of the phenomenon and directly implicating it in the pathogenesis of disease. Specific Aims 1 and 2 focus upon the potential mechanisms underlying the cytoplasmic redistribution of mutant TDP-43. Interestingly, mutations in TARDBP result invariably in symptoms of ALS with motor neuron degeneration, but only rarely in dementia with cortical neuron pathology, suggesting that motor neurons are selectively vulnerable to mutant TDP-43. In Specific Aim 3, I characterize the particular susceptibility of motor neurons to mutant TDP-43. The fundamental goal of the project is to define the pathways involved in mutant TDP43-mediated neurodegeneration, with the ultimate intention of devising therapies with the power to prevent or reverse disease progression. Because TDP-43 deposition is a fundamental property of spontaneous and familial ALS, as well as the most common pathologic subtype of FTD, investigations into TDP-43's contribution to disease pathogenesis will be critical if we are to eventually develop effective therapies. As principal investigator on the project, I have a strong background in neurology and neuroscience, and will have the support of a primary sponsor, a dedicated advisory committee, and two institutions (the Gladstone Institute and the University of California, San Francisco) in the pursuit of this goal. The research described in this application will lay the foundation for my career in the field of neurodegenerative disease. Moreover, with the receipt of this Award, I will gain the opportunity to acquire the skills, knowledge, mentoring, and experience to become a successful and independent physician-scientist.