Mechanisms of Neurodegeneration in ALS

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是运动神经元进行性变性的结果。星形胶质细胞对神经元功能和存活很重要，但星形胶质细胞在ALS发病机制中的确切作用尚不清楚。与神经元相比，星形胶质细胞可以更容易地被替换，因此是再生医学的重点。家族性肌萎缩侧索硬化症是由包括TDP-43在内的单个基因的致病突变引起的。在ALS研究中的一个关键需要是确定星形胶质细胞在疾病基因存在和缺失的情况下如何在运动神经元变性的启动和进展中起作用。利用四环素诱导的基因表达系统，我们创造了在星形胶质细胞中限制性和可逆表达突变TDP-43的转基因大鼠。通过基因芯片分析，我们已经确定了星形细胞基因的表达谱。许多分泌基因在表达突变型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，表达突变TDP-43的星形胶质细胞失去了神经保护功能，获得了神经毒性特性。在这里，我们将进一步确定星形胶质细胞中突变的TDP-43是如何导致转基因大鼠非细胞自主运动神经元死亡的。在神经退行性变的反应中，星形胶质细胞变得活跃，在疾病的发病机制中可能发挥重要作用。越来越多的证据有力地表明，反应性星形胶质细胞具有神经毒性，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由重新激活的星形胶质细胞分泌的可诱导基因。我们将进一步确定反应性星形胶质细胞促进神经变性的途径。这一建议将确定星形胶质细胞在突变型TDP-43存在和不存在的情况下，如何在运动神经元死亡的起始和进展中起作用，从而促进我们对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.