Study on Neurodegeneration Using TDP-43 Transgenic Rats

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。肌萎缩侧索硬化症在平均5年内不可避免地进展到瘫痪和死亡。在为数不多的几种治疗方法中，没有一种能显著延长生命或提高生活质量。开发有效的ALS治疗方法的主要障碍是对疾病机制的有限了解。ALS研究的最新进展是发现了TDP-43蛋白病变和TDP突变。当在转基因啮齿动物中过表达时，突变的TDP-43会导致进行性神经变性，并伴有严重的胶质反应。为了剖析TDP突变导致神经变性的机制，我们发展了可逆表达突变TDP-43的转基因大鼠，在神经元或星形胶质细胞中表达。通过基因芯片分析，我们还在突变型TDP-43转基因大鼠中发现了对胶质反应有反应的候选基因。利用TDP-43转基因大鼠(体内模型)和原代细胞培养(体外模型)作为互补模型，我们将解决以下关于TDP-43发病机制的关键问题：1)胶质反应与TDP突变引起的神经退行性变如何相关；2)突变的TDP-43在星形胶质细胞中的存在是否加速了胶质细胞的激活；3)哪些分子介导了针对TDP突变的胶质反应的传播；4)突变的TDP-43表达如何产生神经毒性；5)突变的TDP-43在星形胶质细胞中的表达如何影响转基因大鼠ALS的发生和发展；6)突变的TDP-43是否是疾病进展所必需的。拟议的研究不仅将为ALS研究开发理想的动物模型，还将为开发针对星形胶质细胞或突变TDP-43的ALS疗法奠定基础。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) results from progressive degeneration of motor neurons. ALS inexorably progresses to paralysis and to death within an average of 5 years. Of the few treatments, none substantially prolongs life or improves the quality of life. A major hurdle to developing effective therapy for ALS is a limited understanding of the disease mechanisms. A recent advance in ALS research comes with the discovery of TDP- 43 proteinopathy and TDP mutation. When overexpressed in transgenic rodents, mutant TDP-43 causes progressive neurodegeneration accompanied by severe glial reaction. To dissect the mechanisms underlying neurodegeneration caused by TDP mutation, we have developed transgenic rats reversibly expressing mutant TDP-43 in neurons or in astrocytes. By microarray analysis, we also have identified candidate genes responsive to glial reaction in mutant TDP-43 transgenic rats. Using TDP-43 transgenic rats (in vivo model) and primary cell cultures (in vitro model) as complementary models, we will resolve the following critical questions regarding TDP-43 pathogenesis: 1) how glial reaction correlates with the neurodegeneration caused by TDP mutation; 2) whether presence of mutant TDP-43 in astrocytes accelerates glial activation; 3) what molecules mediate the propagation of glial reaction in response to TDP mutation; 4) how astrocytes expressing mutant TDP-43 produce neurotoxicity; 5) how expression of mutant TDP-43 in astrocytes affects onset and progression of ALS in transgenic rats; and 6) whether continuous presence of mutant TDP-43 is required for disease progression. Proposed studies will not only develop desirable animal models for ALS research, but also would establish a foundation for developing ALS therapies targeting astrocytes or mutant TDP-43.