Does TDP-43 dysfunction in astrocytes trigger motor neuron degeneration?

星形胶质细胞中的 TDP-43 功能障碍是否会引发运动神经元变性？

• 批准号: 9110354
• 负责人: ZUOSHANG XU
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110354
• 关键词: Amyotrophic Lateral Sclerosis; Animal Model; Astrocytes; C9ORF72; Cell Nucleus; Cells; Cessation of life; Cytoplasm; Cytoskeleton; DNA-Binding Proteins; Disease; Endoplasmic Reticulum; Familial Amyotrophic Lateral Sclerosis; Functional disorder; GLAST Protein; Gene Deletion; Genes; Genetic study; Health; Investigation; Knock-out; Knockout Mice; Light; Mediating; Mitochondria; Modeling; Motor Neurons; Mus; Muscle Weakness; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Nuclear Protein; Oxidative Stress; Paralysed; Pathology; Pathway interactions; Patients; Phenotype; Play; RNA Processing; Role; Spinal Cord; Testing; Toxic effect; Transgenic Mice; Work; age related; base; in vivo; interest; killings; knock-down; motor neuron degeneration; mouse model; mutant; protein TDP-43; research study; response

 DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease), is a fatal neurodegenerative disease that kills motor neurons, leading to paralysis and death. Ten percent of ALS cases are familial and ninety percent are sporadic. Genetic studies have identified multiple causes for the familial ALS, including mutations in SOD1, TDP-43, FUS, UBQLN2, c9orf72 and PFN1 genes. Among these mutant genes, TDP-43 is of particular interest because it is involved in the most ALS cases. TDP-43 intracellular aggregation or TDP-43 proteinopathy, is a prominent pathological feature in the majority (>95%) of ALS cases, including all the sporadic and most of the familial cases. TDP-43 is normally a nuclear protein. But in ALS, TDP-43 accumulates and aggregates in the cytoplasm and is depleted from the nuclei of motor neurons and glia. While TDP- 43 aggregation can harm cells through a gain of toxicity, it could also cause a loss of TDP-43 function by depleting the functional TDP-43 from the nuclei and cytoplasm. TDP-43 maintains its expression level constant by an auto-regulatory mechanism. Perturbation of the level of TDP-43, either by increasing or by decreasing TDP-43 in animal models leads to neurodegeneration and ALS phenotypes. The evidence supports the concept that TDP-43 dysregulation and the consequent TDP-43 dysfunction is a critical driver of neurodegeneration. In recent years, mounting evidence supports the notion that glia play a major role in neurodegeneration. In ALS, most studies have been conducted in models that express mutant SOD1. Investigation on models associated with TDP-43 expression is just beginning and the evidence has been contradictory. Given the potential role of TDP-43 dysfunction in motor neuron degeneration, we have generated a TDP-43 knockdown transgenic mouse model, which has shown the core features of ALS, including age-dependent motor neuron degeneration, muscle weakness and paralysis. An unexpected finding in this mouse model is that TDP-43 was knocked down in astrocytes but the knockdown was undetectable in motor neurons. Based on this result, we hypothesize that TDP-43 dysfunction in astrocytes can drive motor neuron degeneration. We propose to test this hypothesis by generate mice where TDP-43 gene deletion can be induced specifically in astrocytes. By analyzing these mice, we will determine whether a loss of TDP-43 function in astrocytes can cause motor neuron degeneration. The results will shed light on the role of TDP-43 in motor neuron degeneration 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）是一种致命的神经退行性疾病，可杀死运动神经元，导致瘫痪和死亡。10%的ALS病例是家族性的，90%是散发性的。遗传学研究已经确定了家族性ALS的多种原因，包括SOD 1，TDP-43，FUS，UBQLN 2，c9 orf 72和PFN 1基因的突变。在这些突变基因中，TDP-43特别令人感兴趣，因为它涉及大多数ALS病例。TDP-43细胞内聚集或TDP-43蛋白质病是大多数（>95%）ALS病例的突出病理学特征，包括所有散发性和大多数家族性病例。TDP-43通常是一种核蛋白。但在ALS中，TDP-43在细胞质中积累和聚集，并从运动神经元和神经胶质细胞的细胞核中耗尽。虽然TDP- 43聚集可以通过毒性的增加来损害细胞，但是它也可以通过从细胞核和细胞质中耗尽功能性TDP-43而导致TDP-43功能的丧失。TDP-43通过自动调节机制维持其表达水平恒定。在动物模型中，通过增加或减少TDP-43来扰动TDP-43的水平导致神经变性和ALS表型。证据支持TDP-43失调和随之发生的TDP-43功能障碍是神经变性的关键驱动因素的概念。近年来，越来越多的证据支持神经胶质在神经退行性变中起主要作用的观点。在ALS中，大多数研究都是在表达突变SOD 1的模型中进行的。与TDP-43表达相关的模型研究才刚刚开始，证据一直相互矛盾。鉴于TDP-43功能障碍在运动神经元变性中的潜在作用，我们已经产生了TDP-43敲低转基因小鼠模型，其显示了ALS的核心特征，包括年龄依赖性运动神经元变性、肌无力和瘫痪。在该小鼠模型中的一个意外发现是，TDP-43在星形胶质细胞中被敲低，但在运动神经元中检测不到敲低。基于这一结果，我们假设星形胶质细胞中的TDP-43功能障碍可以驱动运动神经元变性。我们建议通过产生可以在星形胶质细胞中特异性诱导TDP-43基因缺失的小鼠来测试这一假设。通过分析这些小鼠，我们将确定星形胶质细胞中TDP-43功能的丧失是否会导致运动神经元变性。该结果将阐明TDP-43在ALS运动神经元变性中的作用。

项目成果

Development of Excipient-Free Freeze-Dryable Unimolecular Hyperstar Polymers for Efficient siRNA Silencing.

• DOI: 10.1021/acsmacrolett.7b00242
• 发表时间: 2017-06
• 期刊: ACS macro letters
• 影响因子: 5.8
• 作者: Liang Zhao;Xiang Wu;Xiaofeng Wang;Chunying Duan;Hongyan Wang;Amol D. Punjabi;Yang Zhao;Yuanwei Zhang;Zuoshang Xu;Haifeng Gao;Gang Han