Elucidating the Mechanisms Underlying Mutant TDP43-induced Neurodegeneration

阐明突变 TDP43 诱导的神经变性的机制

• 批准号: 8725311
• 负责人: Sami Barmada
• 金额: $ 16.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725311
• 关键词: 3-methyladenine; Abbreviations; Advisory Committees; Affect; Age; Amyotrophic Lateral Sclerosis; Autophagocytosis; Award; Behavior; Behavioral; California; Cell Nucleus; Cells; Cessation of life; Characteristics; Clinical; Cytoplasm; DNA-Binding Proteins; Dementia; Deposition; Development; Diagnosis; Disease; Disease Progression; Exhibits; Exons; Familial Amyotrophic Lateral Sclerosis; Fluorescence Microscopy; Foundations; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Genetic; Glycine; Goals; Half-Life; Heterogeneous-Nuclear Ribonucleoproteins; Impaired cognition; In Vitro; Inclusion Bodies; Individual; Institutes; Institution; Intention; Investigation; Karyopherins; Knowledge; Label; Language Disorders; Light; Link; MAP1 Microtubule-Associated Protein; Mediating; Mentors; Modeling; Molecular; Motor Neuron Disease; Motor Neurons; Muscular Atrophy; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurology; Neurons; Neurosciences; Nuclear Export; Nuclear Localization Signal; Nuclear RNA; Optics; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Physicians; Physiologic pulse; Play; Population; Predisposition; Principal Investigator; Process; Property; Protein Isoforms; Proteins; RNA-Binding Proteins; Research; Rodent; Role; San Francisco; Scientist; Signal Transduction; Signs and Symptoms; Specificity; Spinal; Staging; Symptoms; System; Temporal Lobe; Toxic effect; Ubiquitin; Universities; career; cell type; effective therapy; enhanced green fluorescent protein; experience; frontal lobe; hazard; human FRAP1 protein; human Huntingtin protein; immunocytochemistry; insight; mTOR protein; motor neuron degeneration; multicatalytic endopeptidase complex; mutant; neuron loss; neurotoxicity; nucleocytoplasmic transport; polyglutamine; pre-clinical; prevent; protein TDP-43; research study; respiratory; skills; superoxide dismutase 1; therapy design; therapy development

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.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是最常见的运动神经元疾病，尽管100多年前由Jean-Martin Charcot对其进行了首次描述，但仍然没有有效的治疗方法来治疗最终致命的虚弱和肌肉萎缩。同样，我们治疗额颞叶痴呆（FTD）患者的能力也非常有限，FTD是65岁以下人群中第二常见的痴呆类型。尽管临床上存在差异，但大多数ALS和最常见的FTD类型有一个共同的病理学特征，即沉积43 kDa的TAR DNA结合蛋白（TDP-43）。TDP-43（TARDBP）编码基因内突变的鉴定及其与家族性ALS和FTD的相关性表明，TDP-43在疾病发病机制中起着不可或缺的作用。该提案探索了突变型TDP-43诱导神经元丢失的细胞机制，为开发可预防ALS、FTD和其他以TDP- 43蓄积为标志的神经退行性疾病的疗法奠定了基础。 在初步研究中，我们建立了一个可靠的神经元模型的TDP 43-蛋白质病，并验证了该系统概括了疾病的基本特征在体外。此外，我们证明了与家族性ALS相关的TARDBP突变能够通过TDP-43从细胞核（通常集中在细胞核）到细胞质的错误定位引起神经元毒性。TDP-43相同的细胞质再分布是ALS和FTD患者退化神经元的特征，证实了该现象的重要性，并直接暗示其与疾病的发病机制有关。具体目标1和2关注突变TDP-43的细胞质再分布的潜在机制。有趣的是，TARDBP的突变总是导致ALS的症状与运动神经元变性，但很少在痴呆与皮质神经元病理，表明运动神经元选择性地易受突变TDP-43。在具体目标3中，我描述了运动神经元对突变TDP-43的特殊易感性。 该项目的基本目标是确定突变型TDP 43介导的神经退行性变所涉及的途径，最终目的是设计具有预防或逆转疾病进展能力的疗法。由于TDP-43沉积是自发性和家族性ALS的基本性质，也是FTD最常见的病理亚型，因此如果我们最终要开发有效的治疗方法，研究TDP-43对疾病发病机制的贡献将至关重要。作为该项目的主要研究者，我在神经病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（格拉德斯通研究所和加州大学旧金山弗朗西斯科）的支持。本申请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，获得该奖项后，我将有机会获得技能，知识，指导和经验，成为一名成功和独立的医生科学家。