Animal Models for Studying Human Frontotemporal Dementia

描述（由申请人提供）：额颞叶痴呆（FTD）是年龄依赖性痴呆的第二种最常见形式，与额叶和颞叶的局灶性变性相关。这种隐性疾病与阿尔茨海默病（AD）不同。例如，最近的研究表明，FTD患者比AD患者具有更短的生存期和更快的认知和功能下降速率，并且许多患者缺乏AD的病理学特征（Boxer et al.，2005; Neary等人，2005年）。平均而言，FTD在50至60岁仍在工作的患者中发作。因此，这种疾病是一种严重的疾病，对受影响的家庭和社会都构成重大挑战。关于FTD发病机制的遗传和分子机制仍有许多有待了解的地方。FTD具有可变的临床表现，可能涉及多种遗传因素。在一些患者中，微管结合蛋白tau在疾病进展中起着核心作用。然而，许多FTD患者并不表现出tau蛋白病，因此了解其他可能导致这种疾病的遗传途径仍然很重要。CHMP 2B基因的显性突变导致与3号染色体（FTD 3）连锁的家族性FTD。CHMP 2B是酵母蛋白Vps 2的人类直系同源物，Vps 2是ESCRT-III中的关键组分，其对于通过内体-溶酶体途径加工跨膜蛋白是必需的。这些人类突变如何导致神经退行性变仍不清楚。我们的初步结果表明，ESCRT-III功能障碍导致神经元细胞死亡。在这里，我们建议继续使用FTD 3的体外细胞模型和体内苍蝇模型来研究这种神经退行性疾病的分子机制和遗传途径。我们将测试FTD 3突变干扰哺乳动物神经元中ESCRT-III复合物的正常功能的假设。我们还将在果蝇模型中研究FTD相关的神经变性机制。此外，我们将识别和表征遗传修饰剂，以提供进一步的机制见解。

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD), the second most common form of age-dependent dementia, is associated with focal degeneration of the frontal and temporal lobes. This insidious disorder is distinct from Alzheimer's disease (AD). For instance, recent studies indicate that FTD patients have shorter survival and faster rates of cognitive and functional decline than AD patients, and many lack the pathological hallmarks of AD (Boxer et al., 2005; Neary et al., 2005). On average, FTD strikes patients at 50 to 60 years of age who are still in the work force. Therefore, the disorder represents a serious medical condition and imposes a significant challenge both to affected families and to society. Much remains to be learned about the genetic and molecular mechanisms underlying the pathogenesis of FTD. FTD has a variable clinical presentation that likely involves multiple genetic factors. In some patients, the microtubule-binding protein tau plays a central role in disease progression. However, many FTD patients do not exhibit tauopathies, and so it remains essential to understand other genetic pathways whose defects may contribute to this disorder. Dominant mutations in the CHMP2B gene cause a familial form of FTD linked to chromosome 3 (FTD3). CHMP2B is the human ortholog of the yeast protein Vps2, a key component in ESCRT-III, which is essential for the processing of transmembrane proteins through the endosomal-lysosomal pathway. How these human mutations lead to neurodegeneration remains unclear. Our preliminary results indicate that dysfunction of ESCRT-III leads to neuronal cell death. Here we propose to continue to use an in vitro cellular model and an in vivo fly model of FTD3 to investigate the molecular mechanisms and genetic pathways involved in this neurodegenerative disorder. We will test the hypothesis that FTD3 mutations interfere with the normal function of the ESCRT-III complex in mammalian neurons. We will also investigate the mechanisms of FTD-related neurodegeneration in Drosophila models. Moreover, we will identify and characterize genetic modifiers to provide further mechanistic insights.