Mechanisms of Neurodegeneration in ALS

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）由运动神经元的进行性变性引起。星形胶质细胞对于神经元的功能和存活是重要的，但星形胶质细胞如何确切地促进ALS发病机制尚不清楚。与神经元相比，星形胶质细胞更容易被替换，因此是再生医学的焦点。家族性ALS是由个体基因的致病性突变引起的，包括TDP-43。ALS研究中的一个关键需求是确定星形胶质细胞如何在星形胶质细胞中存在和不存在疾病基因的情况下促进运动神经元变性的起始和进展。使用四环素诱导的基因表达系统，我们已经建立了转基因大鼠，限制性和可逆地表达突变TDP-43的星形胶质细胞。通过微阵列分析，我们确定了星形胶质细胞基因的表达谱。许多分泌基因在表达突变TDP-43的星形胶质细胞中被诱导。星形胶质细胞基因的功能分析表明，在表达突变TDP-43的星形胶质细胞中，神经保护功能丧失，神经毒性增加。在这里，我们将进一步确定星形胶质细胞中的突变TDP-43如何导致转基因大鼠的非细胞自主运动神经元死亡。星形胶质细胞对神经退行性变的反应性，可能在疾病的发病机制中发挥重要作用。越来越多的证据强烈表明，反应性星形胶质细胞获得神经毒性特性，但反应性星形胶质细胞如何执行神经毒性仍有待确定。使用各种方法，我们已经确定了一个诱导基因，是由重新激活星形胶质细胞分泌。我们将进一步明确反应性星形胶质细胞促进神经退行性变的途径。该提案将确定星形胶质细胞如何在星形胶质细胞中存在和不存在突变TDP-43的情况下促进运动神经元死亡的启动和进展，推进我们对ALS疾病机制的理解。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) results from the progressive degeneration of motor neurons. Astrocytes are important for neuronal function and survival, but exactly how astrocytes contribute to ALS pathogenesis is not known. Compared to neurons, astrocytes can be replaced much more easily and thus are the focus of regenerative medicine. Familial ALS is caused by pathogenic mutation in individual genes, including TDP-43. A critical need in ALS research is determining how astrocytes contribute to the initiation and progression of motor neuron degeneration in the presence and absence of the disease gene in astrocytes. Using a tetracycline- inducible gene expression system, we have created transgenic rats that restrictedly and reversibly express mutant TDP-43 in astrocytes. By microarray assays, we have determined the expression profiles of astrocytic genes. Many secretory genes are induced in astrocytes expressing mutant TDP-43. Functional analyses of astrocytic genes suggest a loss of neuroprotective functions and a gain of neurotoxic properties in astrocytes expressing mutant TDP-43. Here we will further determine how mutant TDP-43 in astrocytes causes non-cell- autonomous motor neuron death in transgenic rats. In response to neurodegeneration, astrocytes become reactive and may play important roles in disease pathogenesis. Increasing evidence strongly suggests that reactive astrocytes gain neurotoxic properties, but how reactive astrocytes execute neurotoxicity remains to be determined. Using various approaches, we have identified an inducible gene that is secreted by reactivate astrocytes. We will further define the route by which reactive astrocytes use to promote neurodegeneration. This proposal will determine how astrocytes contribute to the initiation and progression of motor neuron death in the presence and absence of mutant TDP-43 in astrocytes, advancing our understanding of ALS disease mechanisms.