Mechanisms of Neurodegeneration in ALS

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是由运动神经元进行性变性引起的。星形胶质细胞对神经元功能和存活很重要，但星形胶质细胞如何参与ALS的发病机制尚不清楚。与神经元相比，星形胶质细胞更容易被替换，因此是再生医学的重点。家族性ALS是由个体基因的致病性突变引起的，包括TDP-43。ALS研究的一个关键需求是确定在星形胶质细胞中存在或不存在疾病基因的情况下，星形胶质细胞如何参与运动神经元变性的发生和进展。利用四环素诱导的基因表达系统，我们建立了在星形胶质细胞中限制性和可逆表达突变体TDP-43的转基因大鼠。通过微阵列检测，我们确定了星形细胞基因的表达谱。许多分泌基因在表达突变体TDP-43的星形胶质细胞中被诱导。星形细胞基因的功能分析表明，在表达突变体TDP-43的星形细胞中，神经保护功能的丧失和神经毒性的增加。在这里，我们将进一步确定星形胶质细胞中突变的TDP-43如何导致转基因大鼠的非细胞自主运动神经元死亡。在神经退行性变中，星形胶质细胞具有反应性，可能在疾病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，是由星形胶质细胞重新激活分泌。我们将进一步确定反应性星形胶质细胞用于促进神经变性的途径。该建议将确定星形胶质细胞在存在和不存在突变体TDP-43的情况下如何促进运动神经元死亡的发生和进展，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.