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

 描述(申请人提供)：肌萎缩侧索硬化症(ALS)，也被称为Lou Gehrig病，是一种致命的神经退行性疾病，杀死运动神经元，导致瘫痪和死亡。10%的肌萎缩侧索硬化症病例是家族性的，90%是散发的。遗传学研究已经确定了家族性ALS的多种原因，包括SOD1、TDP-43、FUS、UBQLN2、C9ORF72和PFN1基因的突变。在这些突变基因中，TDP-43尤其令人感兴趣，因为它与大多数ALS病例有关。TDP-43细胞内聚集或TDP-43蛋白病变是大多数(95%)ALS病例的显著病理特征，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。但在肌萎缩侧索硬化症中，TDP-43在细胞质中聚集和聚集，并从运动神经元和神经胶质细胞的细胞核中被耗尽。虽然TDP-43的聚集可以通过获得毒性来损害细胞，但它也可能通过从细胞核和细胞质中耗尽功能性的TDP-43而导致TDP-43功能的丧失。TDP-43通过一种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来扰乱TDP-43的水平，会导致神经变性和ALS表型。证据支持TDP-43调节失调和随之而来的TDP-43功能障碍是神经退行性变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细胞在神经退行性变中发挥重要作用的观点。在肌萎缩侧索硬化症中，大多数研究都是在表达突变SOD1的模型中进行的。对与TDP-43表达相关的模型的研究才刚刚开始，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，我们建立了TDP-43基因敲除转基因小鼠模型，该模型显示了ALS的核心特征，包括年龄依赖性运动神经元退化、肌肉无力和瘫痪。在这个小鼠模型中，一个意想不到的发现是，TDP-43在星形胶质细胞中被击倒，但在运动神经元中检测不到这种击倒。基于这一结果，我们假设星形胶质细胞中的TDP-43功能障碍可能会导致运动神经元变性。我们建议通过产生TDP-43基因缺失可以在星形胶质细胞中特异性地诱导的小鼠来检验这一假设。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退化。这一结果将有助于阐明TDP-43在ALS运动神经元变性中的作用。

 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.