Modeling TDP-43 Dysfunction in vivo

描述（由申请人提供）：额颞叶痴呆（FTD）是仅次于阿尔茨海默病的第二种最常见的临床痴呆。FTD是由额颞皮质神经元变性引起的，导致这些脑区功能丧失。主要临床症状是难以根据社会需求改变行为，缺乏抑制，冲动和强迫行为，缺乏对他人的关心，个人卫生恶化和进行性语言功能障碍。它与阿尔茨海默病的不同之处在于，这种疾病开始时有轻度或无记忆丧失。只有到疾病的晚期，记忆力才会丧失。约40-50%的FTD病例有家族史，由基因突变引起。已确定突变导致FTD的基因为微管相关蛋白tau（MAPT）、带电多泡体蛋白2B（CHMP 2B）、含血管素蛋白（VCP）和颗粒蛋白前体（PGRN）。这些突变基因如何导致神经元变性尚不清楚。超过一半的患者的共同病理是皮质神经元中的泛素阳性包涵体。最近，TDP-43被鉴定为泛素包涵体的主要成分。TDP-43是一种广泛表达的核蛋白，可能在转录调节、mRNA剪接中起作用，并且可能与SMN相互作用，SMN的突变导致脊髓性肌萎缩。在FTD患者中，TDP-43在具有泛素阳性包涵体的神经元核中减少，表明其功能可能降低。有趣的是，在肌萎缩侧索硬化（ALS）（一种致命的麻痹性疾病）患者的运动神经元中的泛素包涵体中也发现了TDP-43，这表明FTD和ALS可能具有共同的致病机制。为了研究TDP-43的功能及其在FTD中的作用，我们建议应用新开发的转基因RNAi方法来创建TDP-43亚型的小鼠模型。如果成功，我们将产生一种新的FTD动物模型，可用于研究神经退行性变机制和测试这种疾病的治疗策略。TDP-43在FTD和ALS中形成蛋白质聚集体，这两种致命的神经退行性疾病无法治愈。TDP-43的聚集可损害TDP-43的正常功能。我们试图使用RNAi建立TDP-43功能受损的小鼠模型。该模型将测试TDP-43功能降低是否会导致类似于FTD和ALS中发生的神经变性，并将有助于研究FTD和ALS中的神经变性机制。

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is the 2nd most common clinical dementia after Alzheimer's disease. FTD results from neuronal degeneration in the frontal temporal cortices, leading to a loss of functions in these brain regions. The main clinical symptoms are difficulty in modifying behavior based on social demands, lack of inhibition, impulsive and compulsive acts, lack of concern for others, deterioration of personal hygiene and progressive language dysfunction. It differs from Alzheimer's disease in that the disease begins with mild or no memory loss. Only until the late stage of the disease does memory loss emerge. About 40-50% FTD cases have a family history and are caused by genetic mutations. The genes whose mutation have been identified to cause FTD are microtubule-associated protein tau (MAPT), charged multivesicular body protein 2B (CHMP2B), vasolin-containing protein (VCP) and progranulin (PGRN). How these mutant genes cause neuronal degeneration is not known. Common to more than half of the patients is the pathology of ubiquitin-positive inclusions in the cortical neurons. Recently, TDP-43 is identified as a main component in the ubiquitin inclusions. TDP-43 is a ubiquitously expressed nuclear protein that may function in transcription regulation, mRNA splicing and may interact with SMN, whose mutation cause spinal muscular atrophy. In FTD patients, TDP-43 is reduced in the nuclei of the neurons that have the ubiquitin-positive inclusions, suggesting that its function may be reduced. Interestingly, TDP-43 is also found in the ubiquitin inclusions in motor neurons of patients with amyotrophic lateral sclerosis (ALS), a fatal paralytic disease, suggesting that FTD and ALS may share common pathogenic mechanisms. To investigate the function of TDP-43 and its role in FTD, we propose to apply a newly developed transgenic RNAi approach to create a mouse model of TDP-43 hypomorphism. If successful, we will generate a new animal model for FTD, which can be used to investigate the neurodegeneration mechanism and test therapeutic strategies for this disease. PUBLIC HEALTH RELEVANCE TDP-43 forms protein aggregates in FTD and ALS, two fatal neurodegenerative diseases without a cure. The aggregation of TDP-43 can compromise the normal function of TDP-43. We seek to establish a mouse model with compromised TDP-43 function using RNAi. This model will test whether reduced TDP-43 function can cause neurodegeneration similar to what occurs in FTD and ALS and will be useful for studying neurodegeneration mechanism in FTD and ALS.