Elucidating the Mechanisms Underlying Mutant TDP43-induced Neurodegeneration

阐明突变 TDP43 诱导的神经变性的机制

基本信息

批准号：
8477323
负责人：
Sami Barmada
金额：
$ 0.6万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8477323
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

项目摘要

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）：肌萎缩侧索硬化症 (ALS) 是最常见的运动神经元疾病，尽管 Jean-Martin Charcot 早在 100 多年前就对其进行了首次描述，但对于最终致命的无力和典型的肌肉萎缩仍然没有有效的治疗方法的疾病。同样，我们治疗额颞叶痴呆 (FTD) 患者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类型。尽管临床表现存在差异，但大多数 ALS 和最常见的 FTD 类型具有共同的病理学特征，其特征是 43 kDa 的 TAR DNA 结合蛋白 (TDP-43) 的沉积。 TDP-43 (TARDBP) 编码基因内突变的鉴定及其与家族性 ALS 和 FTD 的关联表明，TDP-43 在疾病发病机制中发挥着不可或缺的作用。该提案探索了突变 TDP43 诱导的神经元损失的细胞机制，为开发可预防 ALS、FTD 和其他以 TDP-43 积累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 TDP43 蛋白病的忠实神经元模型，并验证该系统在体外重现了疾病的基本特征。此外，我们证明与家族性 ALS 相关的 TARDBP 突变能够通过 TDP-43 从通常集中的细胞核错误定位到细胞质而引起神经元毒性。 TDP-43 的相同细胞质重新分布是 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 重点关注突变 TDP-43 细胞质重新分布的潜在机制。有趣的是，TARDBP 的突变总是会导致伴有运动神经元变性的 ALS 症状，但很少会导致伴有皮质神经元病理学的痴呆，这表明运动神经元选择性地容易受到突变 TDP-43 的影响。在具体目标 3 中，我描述了运动神经元对突变 TDP-43 的特殊敏感性。该项目的基本目标是确定突变 TDP43 介导的神经变性的途径，最终目的是设计能够预防或逆转疾病进展的疗法。由于 TDP-43 沉积是自发性和家族性 ALS 的基本特性，也是 FTD 最常见的病理亚型，因此如果我们要最终开发出有效的治疗方法，那么研究 TDP-43 对疾病发病机制的贡献至关重要。作为该项目的首席研究员，我在神经病学和神经科学方面拥有深厚的背景，并将得到主要赞助商、专门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分校）的支持。追求这个目标。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，成为一名成功且独立的医师科学家。