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：
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
项目类别：
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

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）：肌萎缩性侧索硬化症（ALS）是最常见的运动神经元疾病，尽管它在100年前由Jean-Martin Charcot进行了100年前的最初描述，但对于最终的致命弱点和肌肉萎缩而言，仍然没有有效的治疗方法。同样，我们治疗额颞痴呆（FTD）的患者的能力是65岁以下个体中第二常见的痴呆症类型。尽管它们的临床差异，但大多数ALS和最普遍的FTD类型具有共同的病理学，其标志为TAR DNA结合蛋白的沉积为43 kDa（TDP-43）。编码TDP-43（TARDBP）的基因中的突变及其与家族ALS和FTD的关联表明TDP-43在疾病发病机理中起着不可或缺的作用。该建议探讨了负责突变体TDP43诱导的神经元丧失的细胞机制，为开发可以预防ALS，FTD和其他由TDP-43积累标记的疗法的疗法奠定了基础。在初步研究中，我们建立了TDP43-蛋白质病的忠实神经元模型，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突变能够通过从通常浓缩的细胞核中TDP-43的错误定位到细胞质引起神经元毒性。 TDP-43的相同细胞质再分布是来自ALS和FTD患者退化神经元的特征，证实了该现象的重要性，并将其直接与疾病的发病机理有关。具体目的1和2集中在突变体TDP-43的细胞质重新分布的潜在机制上。有趣的是，TARDBP的突变总是导致运动神经元变性的ALS症状，但仅在皮质神经元病理的痴呆症中很少表明运动神经元有选择地容易受到突变体TDP-43的影响。在特定的目标3中，我表征了运动神经元对突变体TDP-43的特殊敏感性。该项目的基本目标是定义突变TDP43介导的神经变性的途径，最终意图是设计具有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的最常见病理亚型，因此，如果我们最终要开发有效的治疗方法，对TDP-43对TDP-43对疾病发病机理的贡献的研究将是至关重要的。作为该项目的首席研究者，我在神经病学和神经科学方面具有强大的背景，并将得到主要赞助商，一个专门的咨询委员会的支持，以及两个机构（Gladstone Institute和加利福尼亚大学，旧金山），以实现这一目标。本应用程序中描述的研究将为我在神经退行性疾病领域的职业奠定基础。此外，通过获得该奖项，我将有机会获得成功，独立的医师科学家的技能，知识，指导和经验。