Vacuolar Tauopathy

人类疾病的罕见遗传原因有可能揭示出对更多 常见的散发性疾病。神经细胞骨架tau蛋白的基因MAPT罕见的突变导致 典型的临床表现为额颞部痴呆的家族性变态反应。紧张症是一组 致命的神经系统疾病，包括阿尔茨海默病，神经退化是积聚的结果 病理性tau蛋白聚集体的形式为神经原纤维缠结、Pick小体或神经胶质包涵体。 MAPT突变是唯一已知的常染色体显性遗传性原发变态反应的原因。我们已经确定了一个 伴有tau包涵体的常染色体显性遗传性额颞部退行性变 与一种高度保守的基本基因中的一种新的基因突变有关。我们提出了三个具体目标 了解该基因突变导致tau病理的基本分子机制。我们会 进行研究以确定这种基因突变如何在体外和体内改变tau相互作用和聚集 培养的细胞。我们将扩大这些发现，以确定这种基因突变对内体的影响。 功能，以确定该基因突变是否影响tau聚集体的细胞内播种。最后，我们 将测试这种遗传突变对tau在小鼠中传播的影响，以确定该基因是否 突变增强了tau在体内的毒力。总之，这些机械论研究将阐明基本机制 它们促进了tau病理，从而验证了未来小说发展的新的治疗靶点 抗tau疗法。

Rare genetic causes of human disease have the potential to reveal mechanistic insights into more common sporadic disease. Rare mutations in MAPT, the gene for the neuronal cytoskeleton tau protein, cause familial tauopathies that typically manifest clinically as frontotemporal dementia. Tauopathies are a group of fatal neurologic diseases, including Alzheimer's disease, where neurodegeneration is the result of accumulation of pathologic tau protein aggregates in the form of neurofibrillary tangles, Pick bodies, or glial inclusions. MAPT mutations are the only known cause of autosomal dominant primary tauopathy. We have identified a previously undescribed autosomal dominant form of frontotemporal degeneration with tau inclusions associated with a novel genetic mutation in a highly conserved, essential gene. We propose three specific aims to understand the basic molecular mechanisms by which this gene mutation leads to tau pathology. We will perform studies to determine how this genetic mutation alters tau interactions and aggregation in vitro and in cultured cells. We will extend these findings to determine the effects of this gene mutation on endosomal function to determine whether this gene mutation affects intracellular seeding of tau aggregates. Finally, we will test the effects of this genetic mutation of tau transmission in mice to determine whether this gene mutation enhances tau virulence in vivo. Together, these mechanistic studies will elucidate basic mechanisms which promote tau pathology, thereby validating a novel therapeutic target for future development of novel anti-tau therapies.